Fospropofol methods and compositions

ABSTRACT

The present disclosure pertains to the use of fospropofol, pharmaceutically acceptable salts of fospropofol, or mixtures thereof. Pharmaceutical compositions comprising fospropofol, pharmaceutically acceptable salts of fospropofol, or mixtures thereof, and methods of treating diseases or disorders, including migraine are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the following applications:

-   -   This application is a continuation of U.S. patent application        Ser. No. 17/562,605, filed Dec. 27, 2021, which is:    -   a continuation-in-part of U.S. patent application Ser. No.        17/387,059, filed Jul. 28, 2021, which is a continuation-in-part        of U.S. patent application Ser. No. 17/217,656, filed Mar. 30,        2021;    -   a continuation-in-part of U.S. patent application Ser. No.        17/465,966, filed Sep. 3, 2021, which is a divisional of U.S.        patent application Ser. No. 17/217,656, filed Mar. 30, 2021;    -   a continuation-in-part of U.S. patent application Ser. No.        17/466,016, filed Sep. 3, 2021, which is a continuation of U.S.        patent application Ser. No. 17/217,656, filed Mar. 30, 2021;    -   a continuation-in-part of U.S. patent application Ser. No.        17/168,365, filed Feb. 5, 2021, which claims the benefit of U.S.        Provisional Application No. 62/970,324, filed Feb. 5, 2020;    -   a continuation-in-part of U.S. patent application Ser. No.        17/066,957, filed Oct. 9, 2020, which claims the benefit of U.S.        Provisional Application No. 62/914,051, filed Oct. 11, 2019;    -   a continuation-in-part of U.S. patent application Ser. No.        16/831,035, filed Mar. 26, 2020, which claims the benefit of        U.S. Provisional Application No. 62/824,182, filed Mar. 26,        2019.

The entirety of each of the above forementioned applications isincorporated by reference herein in its entirety.

TECHNICAL FIELD

The present disclosure pertains to the use of propofol prodrugs,pharmaceutically acceptable salts of propofol prodrugs, or mixturesthereof, to treat disease or disorder, including migraine.

The present disclosure also pertains to the use of fospropofol,pharmaceutically acceptable salts of fospropofol, or mixtures thereof,to treat migraine.

The disclosure also pertains to pharmaceutical compositions for oraladministration of fospropofol, or pharmaceutically acceptable salts offospropofol, well as methods for oral administration of fospropofol.

BACKGROUND

Propofol (2,6-diisopropylphenol) is an intravenous short-actinganesthetic agent that has gained acceptance for inducing and maintaininganesthesia and for procedural sedation. Propofol is a highly lipophilicdrug which must be formulated as a suspension with a lipid carrier inaqueous medium. Consequently, propofol derivatives were developed whichpossessed increased water solubility to simplify formulation. One ofthese was fospropofol ((2,6-diisopropylphenoxy)methyl dihydrogenphosphate). Fospropofol is a water-soluble, phosphono-O-methyl prodrugof propofol that was approved in the United States as an alternative topropofol for monitored anesthesia care during procedures.

While intravenous administration is useful for anesthesia applications,oral administration of fospropfol would be desirable for other uses.Oral dosing, however, requires a dosage form having adequatebioavailability with minimal subject-to-subject variability. Thus, thereis a need for dosage forms of fospropofol that are orally bioavailablewith minimal inter-subject variability.

Fospropofol is rapidly metabolized by endothelial alkaline phosphatasesto release propofol, phosphate, and formaldehyde. The small amount offormaldehyde is rapidly converted to formate and safely eliminated,similar to the other available phosphate methyl prodrugs such asfosphenytoin.

Migraine is a primary headache disorder characterized by recurrentheadaches that may be moderate or severe. Typically, the headachesaffect one half of the head, are pulsating in nature, and last from twoto 72 hours.

Migraines are called primary headaches because the pain is not caused byanother disorder or disease such as a brain tumor or head injury.Symptoms of migraines may include nausea, vomiting, and sensitivity tolight, sound, or smell. The pain is generally made worse by physicalactivity. Some cause pain on just the right side or left side of thehead, others result in pain all over. Migraine sufferers may havemoderate or severe pain and usually can't participate in normalactivities because of the pain. Often when a migraine strikes, peopletry to find a quiet, dark room.

Many people have an aura with a migraine, typically a short period ofvisual disturbance that signals that the headache will soon occur.Sufferers have reported seeing flashes or bright spots. Occasionally, anaura can occur with little or no headache following it.

The range of time someone is affected by an attack is often longer thanthe migraine itself, as there is a pre-monitory, or build-up phase, anda post-drome phase that can last one to two days. Different people havedifferent triggers and different symptoms.

Migraines are believed to be due to a mixture of environmental andgenetic factors. Genomics of migraines have been examined and certaingene mutations have been associated with severe migraines, but theetiology is presumably polygenic. Changing hormone levels may also playa role, as migraines affect slightly more boys than girls before pubertyand two to three times more women than men after puberty. Catemanialmigraine is not uncommon in women associated with the menses.

Migraines are believed to involve the nerves and blood vessels of thebrain. However, older ideas that migraines were principally vascular innature are now considered to be incorrect. Although an exact cause isunknown, brain scans show that migraines may be due to “hyperactivity”in parts of the brain. This activity can spread across the cortex duringthe course of the migraine, which is known as spreading corticaldepression.

Migraines are one of the most common causes of disability. There areabout 100 million people with recurrent headaches in the U.S. and about37 million of these people have migraines. The World Health Organizationsuggests that 18 percent of women and 7 percent of men in the U.S.suffer from migraines. Globally, approximately 15% of people areaffected by migraines. Migraines most often start at puberty and getworse during middle age. In some women, migraines become less commonfollowing menopause. Migraine headaches are a common cause of disabilityin the United States, affecting approximately 27 million Americanadults, or 17.1% of women and 5.6% of men.

There is often a distinction between a migraine with an aura and amigraine without an aura. The most current terminology defines a classicmigraine as a migraine with an aura and non-classic or common migraineas a migraine without aura. Also, there is often a distinction betweenchronic migraine and episodic migraine. Chronic migraine, which affects3.2 million Americans (2%), is defined as having at least 15 headachedays a month, with at least 8 days of having headaches with migrainefeatures, and for longer than 3 months in duration. Episodic migraine,in contrast, is a condition defined as having fewer headache days orfewer headache days with migraine features per month.

Migraine treatment may also be characterised as acute treatment orprophylactic (i.e., preventative) treatment. In some embodiments, themethods and pharmaceutical compositions disclosed herein are useful foracute treatment of migraine. In some embodiments, the methods andpharmaceutical compositions disclosed herein are useful for acutetreatment of migraine with or without aura. In other embodiments, themethods and pharmaceutical compositions disclosed herein are useful forprophylactic treatment of migraine.

Current treatments for migraine are divided into acute, abortive agents(analgesics, triptans, ergots, etc.), and medications that are usedchronically to will reduce the frequency and severity of migraineattacks.

Initial recommended treatment is with one of the acute treatments, suchas ibuprofen, naproxen sodium or acetaminophen. Caffeine may also beused for treatment. Nausea medications may also be administered.

Triptans and dihydroergotamine (DHE-45) are also commonly used acutetreatments. The oral triptans [sumatriptan (Imitrex), naratriptan(Amerge), zolmitriptan (Zomig), rizatriptan (Maxalt), almotriptan(Axert), frovatriptan (Frova), and eletriptan (Relpax)] are thought tobe generally effective in only 60 to 70% of patients. Lasmiditan(Reyvow), an oral ditan related to the oral triptans, is used in asimilar fashion to the triptans and has similar efficacy. A largepercentage of migraine sufferers are either resistant to thesemedications or they have unacceptable side effects.

Various NSAID drugs other than ibuprofen and naproxen may also be usedfor acute treatment, such as diclofenac and ketorolac. Opiates aregenerally ineffective and are contraindicated.

Calcitonin gene related peptide (CGRP) receptor targeted small moleculessuch as ubrogepant and rimegepant are newer acute treatments but theyare generally less effective than the triptans although they are bettertolerated.

Many patients require chronic (daily) therapy to prevent migraineattacks. The antidepressant and mood stabilizer Amitriptyline is quiteeffective in some patients, as are beta-blockers including propranololand metoprolol, as well certain antiseizure drugs including topiramate,valproate, and gabapentin.

Antibodies that act on CGRP or its receptor are now also widely used aspreventives. They include Aimovig® (erenumab), Emgality® (galcanezumab),Ajovy® (fremanezumab), and Vyepti (eptinezumab). Although these agentsare effective in many patients, there are many in whom they areineffective. Furthermore, being recombinant biologicals, they areexpensive, and because they are proteins they must be administered byinjection, which does not appeal to some patients.

Quilipta™ (atogepant) along with rimegepant are small molecule CGRPreceptor antagonists that are used chronically, like CGRP antibodies, aspreventives. They are no more effective than the antibodies and manypatients continue to experience unacceptable migraine attacks.

Thus, there is a need for additional methods of treating migraine,particularly refractory migraine.

SUMMARY

The present disclosure provides methods and compositions that meet theneed for additional migraine treatments, including treatments forrefractory migraine.

The disclosure is directed to methods of treating migraine in a patientin need thereof, comprising administering to the patient an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses.

The disclosure is also directed to methods of treating migraine in apatient in need thereof, comprising administering to the patient acomposition comprising an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses.

The disclosure is also directed to pharmaceutical compositionscomprising fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, and a pharmaceutically acceptableexcipient.

The present disclosure provides pharmaceutical dosage forms for oraladministration comprising fospropofol or a pharmaceutically acceptablesalt of fospropofol, and a pharmaceutically acceptable acid.

The disclosure also provides methods of orally administeringfospropofol, or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, the method comprising orally co-administeringfospropofol, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable acid, to the subject.

The present disclosure provides pharmaceutically acceptable salts offospropofol, wherein said salt is a disodium salt.

The present disclosure provides pharmaceutically acceptable salts offospropofol, wherein said salt is a potassium, diethylamine,t-butylamine, ethylene diamine, benzathine, piperazine, ethanolamine,diethanolamine, ammonium, tromethamine, benethamine, histidine, calcium,magnesium, or zinc salt.

The present disclosure also provides pharmaceutical compositionscomprising a fospropofol salt of the disclosure and a pharmaceuticallyacceptable excipient.

The present disclosure also provides methods of treating migraine in apatient in need thereof, comprising administering to the patient aneffective amount of a fospropofol salt of the disclosure.

The present disclosure also provides methods and compositions that meetthe need for additional migraine treatments, including treatments forrefractory migraine.

The disclosure is directed to methods of treating migraine in a patientin need thereof, comprising administering to the patient an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses.

The disclosure is also directed to methods of treating migraine in apatient in need thereof, comprising administering to the patient acomposition comprising an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses.

The disclosure is also directed to pharmaceutical compositionscomprising fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, and a pharmaceutically acceptableexcipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows mean concentration vs. time plots for fospropofol andpropofol by cohort in Part 1 of Study A16.

FIG. 2 shows mean concentrations are plotted over time for fospropofoland propofol by cohort for Part 2 of Study A16.

FIG. 3 shows the Mean (+SD) Fospropofol Plasma Concentrations by Cohort(Fasting Conditions)—Linear Scale—PK Set—Example A16

FIGS. 4A and 4B show an Overlay of Individual and Mean FospropofolPlasma Concentrations by Cohort (Fasting Conditions)—Linear Scale—PKSet—Example A16

FIG. 5 shows an Overlay of Individual and Mean Fospropofol PlasmaConcentrations Food Effect Cohort (Fasting and Fed Conditions)—LinearScale—Example A16

FIG. 6 shows the Mean (±SD) Propofol Plasma Concentrations by Cohort(Fasting Conditions)—Linear Scale—Example A16

FIGS. 7A and 7B show an Overlay of Individual and Mean Propofol PlasmaConcentrations by Cohort (Fasting Conditions)—Linear Scale—Example A16

FIG. 8 shows an Overlay of Individual and Mean Propofol PlasmaConcentrations Food Effect Cohort (Fasting and Fed Conditions)—LinearScale—PK Set—Example A16

FIG. 9 shows the Fospropofol AUC0-t versus Dose (Power Model)—PKSet—Example A16

FIG. 10 shows the Fospropofol AUC0-inf versus Dose (Power Model)—PKSet—Example A16

FIG. 11 shows the Fospropofol Cmax versus Dose (Power Model)—PKSet—Example A16

FIG. 12 shows the Propofol AUC0-t versus Dose (Power Model)—PKSet—Example A16

FIG. 13 shows the Propofol AUC0-inf versus Dose (Power Model)—PKSet—Example A16

FIG. 14 shows the Propofol Cmax versus Dose (Power Model)—PK Set—ExampleA16

FIG. 15 shows the Scatterplots with Linear Regression Line for MOAA/SAgainst Ln-Transformed Propofol Plasma concentrations by Cohort—PKSet—Example A16.

FIG. 16 shows the Scatterplots with Linear Regression Line for BIS scoreAgainst Ln-Transformed Propofol Plasma concentrations by Cohort—PKSet—Example A16.

FIG. 17 shows Linear regression of log Cmax fospropofol on Time toTreatment. Among the migraine subjects there is a trend toward aninverse linear association between log Cmax fospropofol andtime-to-treatment, p=0.067. Values for healthy volunteers are shown onthe left.

FIG. 18 shows Linear regression of log Cmax propofol on Time-toTreatment. Among the migraine subjects there is a statisticallysignificant inverse linear association between log Cmax propofol andtime-to-treatment, p=0.007. Values for healthy volunteers are shown onthe left.

FIG. 19 shows Linear regression of log AUC1 fospropofol onTime-to-Treatment. Among the migraine subjects there is a trend towardan inverse linear association between log AUC1 fospropofol andtime-to-treatment, p=0.098. Values for healthy volunteers are shown onthe left.

FIG. 20 shows Linear regression of log AUC1 propofol onTime-to-Treatment. Among the migraine subjects there is a statisticallysignificant inverse linear association between log AUC1 propofol andtime-to-treatment, p=0.004. Values for healthy Volunteers are shown onthe left.

FIG. 21 shows Linear regression of log AUC2 fospropofol onTime-to-Treatment. Among the migraine subjects there is a trend towardan inverse linear association between log AUC2 fospropofol andtime-to-treatment, p=0.141. Values for healthy volunteers are shown onthe left.

FIG. 22 shows Linear regression of log AUC2 propofol onTime-to-Treatment. Among the migraine subjects there is a statisticallysignificant inverse linear association between log AUC2 propofol andtime-to-treatment, p=0.009. Values for healthy volunteers are shown onthe left.

FIG. 23 shows Linear regression of log AUC4 fospropofol onTime-to-Treatment. Among the migraine subjects there is a trend towardan inverse linear association between log AUC4 fospropofol andtime-to-treatment, p=0.168. Values for healthy volunteers are shown onthe left.

FIG. 24 shows Linear regression of log AUC4 propofol onTime-to-Treatment. Among the migraine subjects there is a statisticallysignificant inverse linear association between log AUC4 propofol andtime-to-treatment, p=0.037. Values for healthy volunteers are shown onthe left.

FIG. 25 shows Linear regression of log of the ratio of AUC1 propofol toAUC1 fospropofol on Time-to-Treatment. Among the migraine subjects thereis a trend toward an inverse linear association between log of the ratioAUC1 propofol to AUC1 fospropofol and time-to-treatment, p=0.150. Valuesfor healthy volunteers are shown on the left. The distribution of thelog of the ratio AUC1 propofol to AUC1 fospropofol was statisticallydifferent between migraine subjects and healthy volunteers, p=0.0367.

FIG. 26 shows Linear regression of log of the ratio of AUC2 propofol toAUC2 fospropofol on Time-to-Treatment. Among the migraine subjects thereis a trend toward an inverse linear association between log of the ratioAUC1 propofol to AUC1 fospropofol and time-to-treatment, p=0.157. Valuesfor healthy volunteers are shown on the left.

FIG. 27 depicts the dissolution profiles of 600 mg fospropofol disodiumsalt acidified tablets in 300 mL of 0.1 N HCl at 37° C.

FIG. 28 depicts the dog propofol plasma profile comparison of 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) without pentagastrin pretreatment; 600 mg fospropofol disodiumtablet with tartaric acid acidifier (Composition A3) withoutpentagastrin pretreatment; and a 1300 mg fospropofol disodium aqueoussolution (30 mg/mL) without pentagastrin pretreatment which propofolplasma concentration is normalized to 600 mg fospropofol disodium. SeeExample B2.

FIG. 29 depicts the dog propofol plasma profile comparison of 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) with pentagastrin pretreatment; and 600 mg fospropofol disodiumtablet control (i.e., no acidifier) with pentagastrin pretreatment. SeeExample B2.

FIG. 30 depicts the propofol plasma profile comparison of 600 mgfospropofol disodium tablet with tartaric acid acidifier (CompositionA3) without pentagastrin pretreatment; and 600 mg fospropofol disodiumtablet control (i.e., no acidifier) with pentagastrin pretreatment.

FIG. 31 depicts the fospropofol plasma profiles from 600 mg fospropofoldisodium tablet with ascorbic acid acidifier (Composition A2) and 600 mgfospropofol disodium control composition (i.e., HMPC capsules, noacidifier) in fasted and fed dogs.

FIG. 32 depicts the propofol plasma profiles from 600 mg fospropofoldisodium tablet with ascorbic acid acidifier (Composition A2) and 600 mgfospropofol disodium control composition (i.e., HMPC capsules, noacidifier) in fasted and fed dogs.

FIG. 33 compares the dissolution profile of the 600 mg fospropofoldisodium tablet with ascorbic acid acidifier (Composition A2) and 600 mg(3×200 mg) fospropofol disodium control composition (i.e., HMPCcapsules, no acidifier).

FIG. 34 shows an X-ray powder diffractogram (XRPD) of a potassium saltof fospropofol.

FIG. 35 shows a differential scanning calorimetry (DSC) profile of apotassium salt of fospropofol.

FIG. 36 shows an X-ray powder diffractogram (XRPD) of a diethylaminesalt of fospropofol (Form II).

FIG. 37 shows an X-ray powder diffractogram (XRPD) of a diethylaminesalt of fospropofol (Form I).

FIG. 38 shows a differential scanning calorimetry (DSC) profile of thediethylamine salt of fospropofol (Form I).

FIG. 39 shows a nuclear magnetic resonance (NMR) spectrum of adiethylamine salt of fospropofol (Form I).

FIG. 40 shows an X-ray powder diffractogram (XRPD) of a t-butylaminesalt of fospropofol.

FIG. 41 shows a differential scanning calorimetry (DSC) profile of at-butylamine salt of fospropofol.

FIG. 42 shows a nuclear magnetic resonance (NMR) spectrum of at-butylamine salt of fospropofol.

FIG. 43 shows an X-ray powder diffractogram (XRPD) of an ethylenediamine salt of fospropofol.

FIG. 44 shows a differential scanning calorimetry (DSC) profile of anethylene diamine salt of fospropofol.

FIG. 45 shows a nuclear magnetic resonance (NMR) spectrum of an ethylenediamine salt of fospropofol.

FIG. 46 shows a differential scanning calorimetry (DSC) profile of thebenzathine salt of fospropofol.

FIG. 47 shows a nuclear magnetic resonance (NMR) spectrum of thebenzathine salt of fospropofol.

FIG. 48 shows an X-ray powder diffractogram (XRPD) of a piperazine saltof fospropofol.

FIG. 49 shows a differential scanning calorimetry (DSC) profile of apiperazine salt of fospropofol.

FIG. 50 shows a nuclear magnetic resonance (NMR) spectrum of apiperazine salt of fospropofol.

FIG. 51 shows an X-ray powder diffractogram (XRPD) of an ethanolaminesalt of fospropofol (Form II).

FIG. 52 shows an X-ray powder diffractogram (XRPD) of an ethanolaminesalt of fospropofol (Form I).

FIG. 53 shows a differential scanning calorimetry (DSC) profile of anethanolamine salt of fospropofol (Form I).

FIG. 54 shows a nuclear magnetic resonance (NMR) spectrum of anethanolamine salt of fospropofol (Form I).

FIG. 55 shows differential scanning calorimetry (DSC) profile of adiethanolamine salt of fospropofol.

FIG. 56 shows a nuclear magnetic resonance (NMR) spectrum of adiethanolamine salt of fospropofol.

FIG. 57 shows an X-ray powder diffractogram (XRPD) of an ammonium saltof fospropofol.

FIG. 58 shows a differential scanning calorimetry (DSC) profile of theammonium salt of fospropofol.

FIG. 59 shows an X-ray powder diffractogram (XRPD) of a tromethaminesalt of fospropofol.

FIG. 60 shows a differential scanning calorimetry (DSC) profile of atromethamine salt of fospropofol.

FIG. 61 shows a nuclear magnetic resonance (NMR) spectrum of atromethamine salt of fospropofol.

FIG. 62 shows an X-ray powder diffractogram (XRPD) of a benethamine saltof fospropofol.

FIG. 63 shows a differential scanning calorimetry (DSC) profile of abenethamine salt of fospropofol.

FIG. 64 shows a nuclear magnetic resonance (NMR) spectrum of abenethamine salt of fospropofol.

FIG. 65 shows an X-ray powder diffractogram (XRPD) of a histidine saltof fospropofol.

FIG. 66 shows a differential scanning calorimetry (DSC) profile of ahistidine salt of fospropofol.

FIG. 67 shows a nuclear magnetic resonance (NMR) spectrum of a histidinesalt of fospropofol.

FIG. 68 shows an X-ray powder diffractogram (XRPD) of a calcium salt offospropofol (Form I).

FIG. 69 shows a thermogravimetric analysis (TGA) profile of a calciumsalt of fospropofol (Form I).

FIG. 70 shows an X-ray powder diffractogram (XRPD) of a calcium salt offospropofol (Form II).

FIG. 71 shows an X-ray powder diffractogram (XRPD) of a calcium salt offospropofol (Form III).

FIG. 72 shows an X-ray powder diffractogram (XRPD) of a magnesium saltof fospropofol.

FIG. 73 shows a differential scanning calorimetry (DSC) profile and athermogravimetric analysis profile (TGA) of a magnesium salt offospropofol.

FIG. 74 shows an X-ray powder diffractogram (XRPD) of a zinc salt offospropofol (Form II).

FIG. 75 shows an X-ray powder diffractogram (XRPD) of a zinc salt offospropofol (Form I).

FIG. 76 shows a differential scanning calorimetry (DSC) profile and athermogravimetric analysis profile (TGA) of a zinc salt of fospropofol(Form I).

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present disclosure may be understood more readily by reference tothe following detailed description of desired embodiments and theexamples included therein. In the following specification and the claimsthat follow, reference will be made to a number of terms which have thefollowing meanings.

Unless indicated to the contrary, the numerical values should beunderstood to include numerical values which are the same when reducedto the same number of significant figures and numerical values whichdiffer from the stated value by less than the experimental error ofconventional measurement technique of the type described in the presentapplication to determine the value.

All ranges disclosed herein are inclusive of the recited endpoint andindependently combinable (for example, the range of “from 2 to 10” isinclusive of the endpoints, 2 and 10, and all the intermediate values).The endpoints of the ranges and any values disclosed herein are notlimited to the precise range or value; they are sufficiently impreciseto include values approximating these ranges and/or values.

As used herein, approximating language may be applied to modify anyquantitative representation that may vary without resulting in a changein the basic function to which it is related. Accordingly, a valuemodified by a term or terms, such as “about” and “substantially,” maynot be limited to the precise value specified, in some cases. In atleast some instances, the approximating language may correspond to theprecision of an instrument for measuring the value. The modifier “about”should also be considered as disclosing the range defined by theabsolute values of the two endpoints. For example, the expression “fromabout 2 to about 4” also discloses the range “from 2 to 4.” The term“about” may refer to plus or minus 10% of the indicated number. Forexample, “about 10%” may indicate a range of 9% to 11%, and “about 1”may mean from 0.9-1.1. Other meanings of “about” may be apparent fromthe context, such as rounding off, so, for example “about 1” may alsomean from 0.5 to 1.4.

In the present disclosure the singular forms “a,” “an,” and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “acompound” is a reference to one or more of such compounds andequivalents thereof known to those skilled in the art, and so forth. Theterm “plurality”, as used herein, means more than one.

Certain features of the disclosure which are, for clarity, describedherein in the context of separate embodiments, may also be provided incombination in a single embodiment. That is, unless obviouslyincompatible or specifically excluded, each individual embodiment isdeemed to be combinable with any other embodiment(s) and such acombination is considered to be another embodiment. Conversely, variousfeatures of the disclosure that are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany sub-combination. Finally, while an embodiment may be described aspart of a series of steps, each said step may also be considered anindependent embodiment in itself, combinable with others.

“Propofol prodrug”, as used herein, refers to a molecule which, whenadministered to a mammal, is converted in vivo to propofol.

As used herein, “propofol” refers to 2,6-diisopropylphenol, which hasthe structure:

As used herein, “fospropofol” refers to (2,6-diisopropylphenoxy)methyldihydrogen phosphate, which has the structure:

The terms “fospropofol disodium”, or “disodium salt of fospropofol”refer to the compound having the structure:

The phrase “propofol prodrug, a pharmaceutically acceptable salt ofpropofol prodrug, or mixtures thereof” is meant to encompass a propofolprodrug alone, a pharmaceutically acceptable salt of propofol alone,mixtures of two or more pharmaceutically acceptable salts of a propofolprodrug, and mixtures of a propofol prodrug and one or morepharmaceutically acceptable salts of a propofol prodrug.

The phrase “fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof” is meant to encompass fospropofolalone, a pharmaceutically acceptable salt of fospropofol alone, mixturesof two or more pharmaceutically acceptable salts of fospropofol, andmixtures and fospropofol and one or more pharmaceutically acceptablesalts of fospropofol.

As used herein, “pharmaceutically acceptable salt of fospropofol” refersto a salt of fospropofol that is pharmaceutically acceptable and thatpossesses the desired pharmacologic activity. Such salts are generallynon-toxic, and may be inorganic or organic base addition salts.Specifically, such salts include: salts formed when at least one acidicproton present in fospropofol either is replaced by at least one metalion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminumion: or by an organic base such as aliphatic, alicyclic, or aromaticorganic amines, such as ammonia, methylamine, dimethylamine,diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine,ethylenediamine, lysine, arginine, ornithine, choline,N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine, N-methylglucamine piperazine,tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and thelike. Examples of pharmaceutically acceptable salts of fospropofolinclude monosodium, monopotassium, disodium, dipotassium salts,diethylamine, t-butyl amine, ethylene diamine, benzathine, piperazine,ethanolamine, diethanolamine, ammonium, tromethamine, benethamine,histidine, calcium, magnesium, and zinc salts. Other exemplary saltsinclude the meglumine, deanol, hydrabamine, 2-diethylaminoethanol,4-(2-hydroxyethyl)-morpholine, 1-(2hydroxylethyl)-pyrrolidone, orimidazole.

A crystal form may be referred to herein as being characterized bygraphical data “as shown in” a Figure. Such data include, for example,powder X-ray diffractograms (XRPD), Differential Scanning Calorimetry(DSC) thermograms, thermogravimetric analysis (TGA) profiles, anddynamic vapor sorption profiles (DVS). As is well-known in the art, thegraphical data potentially provides additional technical information tofurther define the respective solid state form which can not necessarilybe described by reference to numerical values or peak positions alone.Thus, the term “substantially as shown in” when referring to graphicaldata in a Figure herein means a pattern that is not necessarilyidentical to those depicted herein, but that falls within the limits ofexperimental error or deviations, when considered by one of ordinaryskill in the art. The skilled person would readily be able to comparethe graphical data in the Figures herein with graphical data generatedfor an unknown crystal form and confirm whether the two sets ofgraphical data are characterizing the same crystal form or two differentcrystal forms.

The terms “polymorph” or “crystalline form” refer to distinct crystalarrangements of the same chemical composition. The term “form” includespolymorphs, crystalline forms, and non-crystalline (amorphous) solids.

A solid, crystalline form may be referred to herein as “polymorphicallypure” or as “substantially free of any other form.” As used herein inthis context, the expression “substantially free of any other forms”will be understood to mean that the solid form contains about 20% orless, about 10% or less, about 5% or less, about 2% or less, about 1% orless, or 0% of any other forms of the subject compound as measured, forexample, by XRPD. Thus, a solid form of a fospropofol salt describedherein as substantially free of any other solid forms would beunderstood to contain greater than about 80% (w/w), greater than about90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w),greater than about 99% (w/w), or about 100% of the subject solid form ofthe fospropofol salt. Accordingly, in some embodiments of thedisclosure, the described solid forms of fospropofol salts may containfrom about 1% to about 20% (w/w), from about 5% to about 20% (w/w), orfrom about 5% to about 10% (w/w) of one or more other solid forms offospropofol salts.

As used herein, unless stated otherwise, XRPD peaks reported herein aremeasured using CuKα radiation, λ=1.5419 Å.

The terms “subject,” or “patient” are used herein to refer to an animal,for example a human, to whom treatment, including prophylactictreatment, with the pharmaceutical compositions or methods according tothe present invention, is provided. The terms “subject” or “patient” asused herein refers to human and non-human animals.

As used herein, the term “treating” means reducing or eliminating thesigns or symptoms of the condition for which fospropofol is beingadministered. In some embodiments, as applied to migraine, the term“treating” (or “treatment”), as used herein, refers to preventing,delaying the onset of, reducing the severity of, or eliminating eitherthe patient's migraine or one or more of the patient's migrainesymptoms. Migraine symptoms can include pain, nausea/vomitting,photophobia, and phonophobia.

The terms “reducing” or “reducing or eliminating” as used herein bothencompass eliminating (i.e., reducing to zero (or none, absent)). Thus,where the term “reducing” is used alone, eliminating may also beencompassed.

The terms “administering” or “administration”, as used herein, refer todelivering fospropofol into or onto the patient's body in a manner thatresults in the presence of propofol in the patient's systemiccirculation. Any such method of administering may be used in performingthe methods of the present disclosure. In some embodiments of thedisclosed methods, the administering is oral, peroral, subcutaneous,intramuscular, intravenous, transmucosal, sublingual, buccal,transdermal, intraintestinal, rectal, or intrapulmonary.

As used herein, the term “orally co-administering” refers tosimultaneous administration, or sequential administration in such amanner that the fospropofol, or a pharmaceutically acceptable saltthereof, and the pharmaceutically acceptable acid are present in thesubject's stomach at the same time.

The term “migraine,” as used herein, refers to a chronic neurovasculardisorder characterized by recurrent attacks of often severe headache(“migraine attacks”), typically accompanied by nausea and sensitivity tolight and/or sound. Migraine is a clinical diagnosis, criteria for whichwould be known and understood by those practicing in the treatment ofmigraine, and would include, for example, the criteria proposed by theInternational Headache Society (IHS). Seehttp://ihs-classification.org/en/.

“Migraine with aura” is migraine characterized by focal neurologicalsymptoms that typically precede, or sometimes accompany, the headache.

“Migraine without aura” is migraine characterized by the absence offocal neurological symptoms that typically precede, or sometimesaccompany, the headache.

“Refractory migraine,” as used herein, refers to migraine that fails torespond to pharmacologic treatment. Failure to respond in this regardincludes, for example, failure of a pharmacological treatment toeliminate migraine pain, as well as failure of a pharmacologicaltreatment to reduce severe or moderate migraine pain to mild migrainepain. Refractory migraine may fail to respond to one or more types ofpharmacologic treatment, for example, acute pharmacologic treatment.Examples of pharmacologic treatments to which refractory migraine mayfail to respond include nonsteroidal anti-inflammatory agents (e.g.ibuprofen, naproxen sodium diclofenac, ketorolac), CGRP inhibitors(e.g., gepants rimegepant, ubrogepant and atogepant; anti-CGRP oranti-CGRP receptor antibodies), dihydroergatime mesylate, and triptans(e.g., sumatriptan (Imitrex), rizatriptan (Maxalt), almotriptan (Axert),naratriptan (Amerge), zolmitriptan (Zomig), frovatriptan (Frova) andeletriptan (Relpax)).

The term “effective amount” or “therapeutically effective amount”, asused herein, refers to an amount sufficient to reduce or eliminate thesigns or symptoms of the condition for which fospropofol is beingadministered. The therapeutically effective amount may be contained in asingle dosage form, or may be the cumulative amount contained inmultiple dosage forms.

The term “effective amount”, as used with respect to methods of treatingmigraine, refers to an amount sufficient to reduce or eliminate thepatient's migraine pain, to eliminate the patient's most bothersomesymptom (“MBS”), or to both reduce or eliminate the patient's migrainepain, and to eliminate the patient's MBS. The effective amount may bethe amount given in a single dose, or may be the cumulative amount givenin multiple doses.

The term “most bothersome symptom” (or “MBS”), is the migraine symptom,other than pain, that is most bothersome to the patient. Examples of MBSinclude nausea, photophobia, and phonophobia.

The term “bothersome symptom” is a migraine symptom, other than pain,that is bothersome to the patient. Examples include nausea, photophobia,and phonophobia.

As used herein, “photophobia” refers to sensitivity to light.

As used herein, “phonophobia” refers to sensitivity to sound.

As used herein, “hypotention” refers to a fall from baseline bloodpressure greater than 20 mm Hg systolic or 20 mm diastolic.

As used herein, the terms “pain relief,” “relief from pain,” “relieffrom headache pain,” or “headache pain relief” refer to eithereliminating pain or reducing severe or moderate pain to mild pain.

As used herein, the term “within” as used to characterize a period oftime (e.g., “within 2 hours”) includes the specified time point as wellas any time points prior to the specified time point. For example,“within 2 hours” includes the time point 2 hours, as well as, forexample, 15 minutes, 30 minutes, 1 hour, and 1.5 hours.

As used herein, the term “pulsatile release” refers to a release inwhich the fospropofol is released from the dosage form in two or moreportions, with periods of time between subsequent releases in whichlittle or no drug release takes place propofolpropofol. A pulsatilerelease dosage form is prepared by, for example, combining an immediaterelease portion with a delayed release portion; or combining two or moredelayed release portions wherein each portion releases drug at adifferent time following administration. Examples of dosage forms thatprovide pulsatile release include capsules containing immediate releasegranules and delayed release granules; bilayer tablets having animmediate release layer and a delayed-release layer.

The term “modified release” as used herein, refers to a dosage form inwhich the release of drug is modified relative to an immediate releasedosage form.

As used herein, the term “extended release dosage form” refers to adosage form that releases the encompassed fospropofol over an extendedperiod of time.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier,diluent, or release modifier to facilitate administration of an agentand that is compatible therewith.

The term “dose”, as used herein, refers to an amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,administered to the patient at a point in time. A dose may beadministered in a single dosage form (e.g., tablet, capsule, etc.), orin multiple dosage forms. For example, an 800 mg “dose” of fospropofolmay be administered in a single 800 mg tablet, in two 400 mg tablets, orin a 600 mg tablet and a 200 mg capsule. In other aspects, a dose may beadministered via a modified release dosage form that releases a firstamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, to the patient at a point or period intime, followed by a second amount fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, to the patient atanother point or period in time. Thus, a modified-release dosage formprovides a single dose that approximates administering multiple separatedoses.

The term “Cmax”, as used herein, refers to the peak concentration of acompound (e.g., propofol or fospropofol) observed in the patient'splasma following administration of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof. The concentrationof propofol in the subject's plasma samples can be determined usingstandard analytical methods.

The term “mean Cmax”, as used herein, refers the mean (arithmetic orgeometric) Cmax in a population. The concentration of propofol or offospropofol in the patient's plasma samples can be determined usingstandard analytical methods.

The term “plasma concentration”, as used herein, refers to the quantityof compound (e.g., propofol or fospropofol) per unit volume of plasma.The term “mean concentration”, as used herein, refers to the mean(arithmetic or geometric) plasma concentration in a population.

The term “AUC_(0-tau)”, (or “AUCt”) as used herein, refers to the areaunder the plasma concentration-time curve from time zero to time t(AUC_(0-tau)), where tau is the last time point with measurableconcentration of the analyte (i.e., propofol or fospropofol).

The term “AUC_(0-∞)”, as used herein, refers to the area under thepatient's plasma concentration-time curve from time zero to timeinfinity (AUC_(0-∞)), where AUC_(0-∞)=AUC_(0-tau)+C_(tau)/λ_(z), C_(tau)is the last measurable drug concentration and λ_(z) is the terminal orelimination rate constant calculated according to an appropriate method.Thus, AUC∞ refers to the AUC obtained by extrapolation of AUC₀ to ∞.

The term “mean AUC_(0-∞)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(0-∞) in a population.

The term “AUC_(2hr)”, as used herein, refers to the partial AUC at time2 hr, i.e., the area under the patient's plasma concentration-time curvefrom time zero to time 2 hours.

The term “mean AUC_(2hr)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(2hr) in a population.

The term “AUC_(1hr)”, as used herein, refers to the partial AUC at time1 hr, i.e., the area under the patient's plasma concentration-time curvefrom time zero to time 1 hour.

The term “mean AUC_(1hr)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(1hr) in a population.

The term “AUC_(4hr)”, as used herein, refers to the partial AUC at time4 hr, i.e., the area under the patient's plasma concentration-time curvefrom time zero to time 4 hours.

The term “mean AUC_(4hr)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(4hr) in a population.

The term “AUC_(20min)”, as used herein, refers to the partial AUC attime 20 minutes, i.e., the area under the patient's plasmaconcentration-time curve from time zero to time 20 minutes.

The term “mean AUC_(20min)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(20min) in a population.

The term “AUC_(30min)”, as used herein, refers to the partial AUC attime 30 minutes, i.e., the area under the patient's plasmaconcentration-time curve from time zero to time 30 minutes.

The term “mean AUC_(30min)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(30min) in a population.

The term “AUC_(60min)”, as used herein, refers to the partial AUC attime 60 minutes, i.e., the area under the patient's plasmaconcentration-time curve from time zero to time 60 minutes.

The term “mean AUC_(60min)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(60min) in a population.

The term “AUC_(120min)”, as used herein, refers to the partial AUC attime 120 minutes, i.e., the area under the patient's plasmaconcentration-time curve from time zero to time 120 minutes.

The term “mean AUC_(120min)”, as used herein, refers to the mean(arithmetic or geometric) AUC_(120min) in a population.

The term “C₂₀”, as used herein, refers to the concentration of analyte(i.e., propofol or fospropofol) in a patient's plasma at the time point20 minutes following administration.

The term “mean C₂₀”, as used herein, refers to the mean (arithmetic orgeometric) C₂₀ in a population.

The term “C₃₀”, as used herein, refers to the concentration of analyte(i.e., propofol or fospropofol) in a patient's plasma at the time point30 minutes following administration.

The term “mean C₃₀”, as used herein, refers to the mean (arithmetic orgeometric) C₃₀ in a population.

The term “C₆₀”, or “C_(1hr)”, as used herein, refers to theconcentration of analyte (i.e., propofol or fospropofol) in a patient'splasma at the time point 60 minutes following administration.

The term “mean C₆₀”, as used herein, refers to the mean (arithmetic orgeometric) C₆₀ in a population.

The term “C₁₂₀”, or “C_(2hr)”, as used herein, refers to theconcentration of analyte (i.e., propofol or fospropofol) in patient'splasma at the time point 120 minutes (i.e., 2 hours) followingadministration.

The term “mean C₁₂₀”, or “mean C_(2hr)”) as used herein, refers to themean (arithmetic or geometric) C₁₂₀ (or “mean C_(2hr)”) in a population.

The term “Tmax” as used herein, refers to the time interval from theadministration of the first dose to the time at which Cmax occurs.

The term median Tmax refers to the median Tmax observed in a population.

The term “plasma concentration”, as used herein, refers to the quantityof compound (e.g., propofol or fospropofol) per unit volume of plasma.

The term “mean concentration”, as used herein, refers to the mean(arithmetic or geometric) plasma concentration in a population.

Two treatments (e.g. 2 formulations, male vs. female, etc.) are notdifferent from one another (i.e., are “bioequivalent”) if the 90%confidence interval of the ratio of a log-transformed exposure measure(AUC and/or C_(max)) falls completely within the range 80-125%.

If a pharmacokinetic parameter set forth herein (e.g., Ctau, Cmax,AUCtau, etc.) does not specify either “plasma” or “mean”, then the termincludes either plasma or mean.

Methods of Treating Migraine

In some aspects, the present disclosure is directed to methods oftreating migraine in a patient in need thereof, comprising administeringto said patient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses.

In other aspects, the present disclosure is directed to methods oftreating migraine in a patient in need thereof, comprising administeringto said patient a composition comprising an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, in one or more doses.

In some aspects, the methods of the disclosure are directed to treatingmigraine.

In some embodiments, the patient's migraine is migraine with aura.

In other embodiments, the patient's migraine is migraine without aura.

In other embodiments, the patient's migraine is migraine is clusterheadache.

In other embodiments, the patient's migraine is migraine is intractablemigraine.

In some embodiments of the disclosed methods, the patient's migraine isrefractory migraine.

Refractory migraine may fail to respond to one or more types ofpharmacologic treatment. Examples of pharmacologic treatment to whichrefractory migraine may fail to respond include CGRP inhibitors (e.g.,gepants, anti-CGRP antibodies), and triptans (e.g., sumatriptan(Imitrex), rizatriptan (Maxalt), almotriptan (Axert), naratriptan(Amerge), zolmitriptan (Zomig), frovatriptan (Frova) and eletriptan(Relpax)).

In some embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to CGRP inhibitors, and is referred to asCGRP inhibitor-refractory migraine.

In some embodiments, the patient's CGRP-inhibitor refractory migrainefails to respond to gepant treatment, and is referred to asgepant-refractory migraine. In other embodiments, the patient'sCGRP-inhibitor refractory migraine fails to respond to anti-CGRPantibodies, and is referred to as anti-CGRP antibody-refractorymigraine.

In other embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to triptans, and is referred to astriptan-refractory migraine.

In other embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to NSAIDs and is referred to asNSAID-refractory migraine.

In other embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to dihydroegotamine (DHE) and is referredto as DHE-refractory migraine.

In some aspects, the methods of the disclosure are directed to treatingmigraine in a patient in need thereof. The methods of the disclosure,therefore, are performed on patients suffering from migraine.

In some embodiments, the patient is a mammal.

In other embodiments, the patient is a human.

In some embodiments, the patient is female.

In other embodiments, the patient is male.

In some embodiments, the patient is 18 years of age or older.

In other embodiments, the patient is between 6 and 17 years of age.

In some embodiments, the patient was diagnosed with migraine at leastone year prior to being administered forpropofol in accordance with thedisclosed methods.

In some aspects, the methods of the disclosure comprise administering tothe patient an effective amount of a propofol prodrug, apharmaceutically acceptable salt of a propofol prodrug, or mixturesthereof.

Examples of propofol prodrugs can be found in, for example, U.S. Pat.No. 6,204,257; Kumnpulainen, Hanna, et al. “Synthesis, in vitro and invivo characterization of novel ethyl dioxy phosphate prodrug ofpropofol.” European journal of pharmaceutical sciences 34.2-3 (2008):110-117; and Baker, Max T. Mohamed Naguib, and David C. Waritier.“Propofol: the challenges of formulation.” The Journal of the AmericanSociety of Anesthesioiogists 103.4 (2005): 860-876.

In some aspects, the methods of the disclosure comprise administering tothe patient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof.

In other embodiments, the methods of the disclosure compriseadministering to the patient an effective amount of a propofol prodrug,a pharmaceutically acceptable salt of a propofol prodrug, or mixturesthereof, wherein the propofol prodrug is sodium2-(2-(2,6-diisopropylphenoxy)-2-oxoethoxy)acetate;(Azepan-1-ylcarbamoylmethyl)carbamic acid 2,6-diisopropylphenyl esterhydrochloride; (E)-3-(2,6-diisopropylphenoxy)acrylic acid;(0-[2-carboxyethyl]-propofol),(S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid;(S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acidmesylate salt;(S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acidhydrochloride;{1-[3-(2,6-diisopropylphenoxy)-3-oxo-2(R)-fluoro-1-propyl]} phosphatemonoester dipotassium salt;{1-[4-(2,6-diisopropylphenoxy)-4-oxo-2(R)-trifluoromethyl-1-butyl]}phosphate monoester dilithium salt;{1-[4-(2,6-diisopropylphenoxy)-4-oxo-3-(R)-3-trifluoromethyl-1-butyl]}phosphate monoester dilithium salt;{1-[4-(2,6-diisopropylphenoxy)-4-oxo-3-(R,S)-3-fluoro-1-butyl]}phosphate monoester dipotassium salt;{1-[4-(2,6-diisopropylphenoxy)-4-oxo-3-(S)-3-fluoro-1-butyl]} phosphatemonoester disodium salt;{1-[6-(2,6-diisopropylphenoxy)-6-oxo-5-(S)-difluoromethyl-1-hexyl]}phosphate diarginine salt;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-1-ium iodide;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(hydroxycarbamoyl)pyridin-1-ium iodide;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methoxycarbonyl)pyridin-1-iumiodide;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methoxycarbonyl)pyridin-1-iummethanesulfonate; 1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methylcarbamoyl)pyridin-1-ium tetrafluoroborate;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methylcarbamoyl)pyridin-1-iumnitrate;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methylcarbamoyl)pyridin-1-iumchloride;1-((((2,6-diisopropylphenoxy)earbonyl)oxy)methyl)-4-formyl-3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-1-iumiodide;1-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-N,N-dimethyl-methanariniumiodide; 1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)-3-(dimethylcarbamoyl)pyridinium mesylate;1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)-3-(methylcarbamoyl)pyridinium mesylate;1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)-3-(methylcarbamoyl)pyridinium iodide;1-((2′,6′-diisopropylphenoxy)carbonylamino)ethyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside;1-((2′,6′-diisopropylphenoxy)carbonylamino)ethyl-β-D-glucopyranoside;1-((2′,6′-diisopropylphenoxy)carbonyloxy)ethyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside;1-((2′,6′-diisopropylphenoxy)carbonyloxy)ethyl-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside;1-((2′,6′-diisopropylphenoxy)carbonyloxy)ethyl-hepta-O-acetyl-β-D-maltose;1-((2′,6′-diisopropylphenoxy)carbonyloxy)ethyl-α-D-glucopyranoside;1-((2′,6′-diisopropylphenoxy)carbonyloxy)ethyl-β-D-maltose;1-((2′,6′-diisopropylphenoxy)carbonyloxy)ethyl-β-n-glucopyranoside;1-((2′,6′-diisopropylphenoxy)carbonyloxy)propyl-2,3,4,6-tetra-O-acetyl-p-D-glucopyranoside;I-((2′,6′-diisopropylphenoxy)carbonyloxy)propyl-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside;1-((2′,6′-diisopropylphenoxy)carbonyloxy)propyl-hepta-O-acetyl-3-D-maltose;1-((2′,6′-diisopropylphenoxy)carbonyloxy)propyl-α-D-glucopyranoside-1-((2′,6′-diisopropylphenoxy)carbonyloxy)propyl-β-D-glucopyranoside:1-((2′,6′-diisopropylphenoxy)carbonyloxy)propyl-β-D-maltose;1-Amino-2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethane;2-[2,6-(Diisopropyl)phenoxy carbonyloxy]ethyl(2S)-2-amino-3-hydroxypropionamide;2-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-N,N-dimethylethan-1-aminiumiodide;2-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N,N,N-trimethylethan-1-aminiumiodide;2-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N,N,N-trimethylethan-1-aminiummethanesulfonate; 2-(2,6-diisopropylphenoxy)-2-hydroxyethylphosphate;2-(2,6-diisopropylphenoxy)-3,4,5-trihydroxy tetrahydropyran-6-yl,dihydrogen phosphate;2-(2,6-diisopropylphenxoy)-3,4,5-trihydroxytetrahydropyran-6-yldihydrogen phosphate arginine. 2,6-(diisopropyl)phenyl1-[((2S)-2-amino-(3R)-3-hydroxy butyryl)aminomethyl]-1-cyclohexaneacetate; 2,6-(diisopropyl)phenyl1-[((2S)-2-amino-3-hydroxypropionyl)aminomethyl]-1-cyclohexane acetate;2,6-(diisopropyl)phenyl1-[((2S)-2-amino-3-methylbutyryl)aminomethyl]-1-cyclohexane acetate;2,6-(diisopropyl)phenyl4-[(2S)-2,3-diaminopropionylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2,6-diaminohexanoylamino]-3,3-dimethylbutanoate;2,6-(Diisopropyl)phenyl4-[(2S)-2-amino-(3R)-3-hydroxylbutyryl]aminobutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-(3R)-3-hydroxybutyryl]amino-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-(3R)-3-hydroxylbutyryl]aminobutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-(4-hydroxyphenyl)propionylamino]-3,3-dimethylbutanoate;2,6-(Diisopropyl)phenyl4-[(2S)-2-amino-(indol-3-yl)propionylamino]-3,3-dimethylbutanoate;2,6-(Diisopropyl)phenyl4-[(2S)-2-amino-3-carbamoylpropionylamino]butanoate;2,6-(Diisopropyl)phenyl4-[(2S)-2-amino-3-hydroxypropionylamino]butanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-3-carbamoylpropionylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-3-carbamoylpropionylamino]butanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-3-carboxypropionylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-3-hydroxypropionylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-3-hydroxypropionylamino]butanoate;2,6-(Diisopropyl)phenyl4-[(2S)-2-amino-3-hydroxypropionylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-amino-3-methylbutyrylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl 4-[(2S)-2-amino-3-methylbutyrylamino]butanoate:2,6-(diisopropyl)phenyl4-[(2S)-2-amino-4-carboxybutyrylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl 4-(2S)-2-amino-4-carboxylbutyrylamino]butanoate;2,6-(diisopropyl)phenyl4-[(2S)-2-aminopropionylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl4-[(2S)-pyrrolidin-2-ylcarbonylamino]-3,3-dimethylbutanoate;2,6-(diisopropyl)phenyl 4-[(2S)-pyrrolidin-2-ylcarbonylamino]butanoate;2,6-(Diisopropyl)phenyl4-[(2S)-pyrrolidin-2-ylcarbonylarainol-3,3-dimetliylbutanoate;2,6-(diisopropyl)phenyl4-[aminomethylcarbonylamino]-3,3-dimethylbutanoate;2,6-(Diisopropyl)phenyl1-[((2S)-2-amino-(3R)-3-hydroxybutyryl)aminomethyl]-1-cyclohexaneacetate; 2,6-(Diisopropyl)phenyl1-[((2S)-2-amino-3-hydroxypropionyl)aminomethyl]-1-cyclohexane acetate;2,6-(Diisopropyl)phenyl1-[((2S)-2-amino-3-methylbutyryl)aminomethyl]-1-cyclohexane acetate;2,6-diisopropylphenyl4-((2-(2-methylpyrazolidin-1-yl)ethyl)amino)-4-oxobutanoate;2,6-diisopropylphenyl4-((2-(4,5-dihydro-1H-pyrazol-1-yl)ethyl)amino)-4-oxobutanoate;2,6-diisopropylphenyl4-((2-(4-ethylpiperazin-1-yl)ethyl)amino)-4-oxobutanoate;2,6-diisopropylphenyl4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-4-oxobutanoate;2,6-diisopropylphenyl 4-((2-morpholinoethyl)amino)-4-oxobutanoate;2,6-Diisopropylphenyl4-(2-(Tert-Butoxycarbonylamino)Propanoyloxy)Butanoate;2,6-Diisopropylphenyl 4-(2-Aminoacetoxy) Butanoate Trifluoroacetic AcidSalt; 2,6-Diisopropylphenyl 4-(2-Aminopropanoyloxy)ButanoateHydrochloride; 2,6-Diisopropylphenyl 4-Hydroxybutanoate;2,6-diisopropylphenyl 4-oxo-4-((2-(piperazin-1-yl)ethyl)amino)butanoate;2,6-diisopropylphenyl 4-oxo-4-((2-(piperidin-1-yl)ethyl)amino)butanoate;2,6-diisopropylphenyl4-oxo-4-((2-(pyrazolidin-1-yl)ethyl)amino)butanoate;2,6-diisopropylphenyl4-oxo-4-((2-(pyrrolidin-1-yl)ethyl)amino)butanoate;2,6-diisopropylphenyl 4-oxo-4-((2-thiomorpholinoethyl)amino)butanoate;2-[2,6-(diisopropyl)phenoxycarbonylamino]ethyl(2S)-2-amino-3-carboxypropionamide;2-[2,6-(diisopropyl)phenoxycarbonylamino]ethyl(2S)-2-amino-3-hydroxypropionamide;2-[2,6-(diisopropyl)phenoxycarbonylamino]ethyl(2S)-2-amino-3-methylbutanoylamide;2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethyl(2S)-2,6-diaminohexanoylamide;2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethyl(2S)-2-amino-(4-hydroxyphenyl)propionamide;2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethyl(2S)-2-amino-(4-hydroxyphenyl)propionamide;2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethyl(2S)-2-amino-3-carbamoylpropionate:2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethyl(2S)-2-amino-3-carbamoylpropionamide;2-[2,6-(Diisopropyl)phenoxycarbonyloxy]ethanol;1-Ammo-2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethane;2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethyl(2S)-2-amino-3-hydroxypropionate;2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethyl (2S)-2-amino-3-hydroxypropionamide; 2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethyl glycinamide;2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate;2-amino-3-methyl-3-(2,6-diisopropyl-phenoxycarbonyloxy)-propanoic acid;3-(((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)carbamoyl)-1-methylpyridin-1-ium iodide;3-((2,6-diisopropylphenoxy)carbonyl)-1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)pyridin-1-ium methanesulfonate;3-{[2-[2,6-Bis(isopropyl)phenoxycarbonyl]-benzoyl]amino}-propanoic acid;3-{[2-[2,6-Bis(isopropyl)phenoxycarbonyloxy|-benzoyl]amino}-propanoicacid;3-carbamoyl-1-((((2,6-diisopropyl-phenoxy)carbonyl)oxy)methyl)pyridin-1-iumiodide; 3-carbamoyl-1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)pyridinium mesylate; 3-carboxy-1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)pyridin-1-ium iodide;3-carboxy-1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)pyridin-1-ium methanesulfonate;4-[(2S)-2-amino-(3R)-3-hydroxybutyryl]amino-3,3-dimethylbutanoate;4-[(2S)-2-amino-3-carbamoylpropionylamino]-3,3-dimethylbutanoate;4-[(2S)-2-amino-4-carboxybutyrylamino]-3,3-dimethylbutanoate;4-[(2S)-2-aminopropionylaminol-3,3-dimethylbutanoate;2,6-(Diisopropyl)phenyl;4-[aminomethylcarbonylamino]-3,3-dimethylbutanoate;2,6-(Diisopropyl)phenyl; arginine 2-(2,6-diisopropylphenoxy)-2-hydroxyethylphosphate; arginine 2-(2,6-diisopropylphenoxy)-3,4,5-trihydroxytetrahydropyran-6-yl dihydrogen phosphate; Boc-Asp(OPropofol)-OBzl;Boc-Asp(OPropofol)-OH; Boc-Glu(OPropofol)-OBzl; Boc-Glu(OPropofol)-OH;di[propofol 5-carboxyl-2(S)-fluorohexanoate] zinc salt; di[propofol5-carboxyl-2-(S)-fluorohexanoate] zinc salt; di[propofol7-carboxyl-2(R,S)-fluorocaprylate] calcium salt; di[propofol7-carboxyl-2-(R,S)-fluorocaprylate] calcium salt; disodiumlauryl-imino-dipropionate 2-(2,6-diisopropylphenoxy)tetrahydropyran-6-yl dihydrogen phosphate; disodiumlauryl-imino-dipropionate-2-(2,6-diisopropylphenoxy)tetrahydropyran-6-yl dihydrogen phosphate; H-Abu-Asp(OPropofol)-OH;H-Abu-Thr(γ-OC(O)OPropofol)-OHL Hydrochloride; H-Aib-OCH₂OPropofol;H-Ala-Asn-OPropofol; H-Ala-Asp(OCH₂OPropofol)-OH;H-Ala-Asp(OPropofol)-OH; H-Ala-Cys(β-SC(O)OPropofol)-OH;H-Ala-Glu(OPropofol)-OH; H-Ala-OPropofol Hydrochloride;H-Ala-Phe-OPropofol; H-Ala-Ser(β-OC(O)OPropofol)-OH;H-Ala-Thr(β-OC(O)OPropofol)-OH; H-Ala-Thr(γ-OC(O)OPropofol)-OHHydrochloride; H-Ala-Tyr-OPropofol; H-Arg-Asp(OPropofol)-OH;H-Arg-Phe-OPropofol; H-Arg-Thr(γ-OC(O)OPropofol)-OH Tris-Hydrochloride;H-Asn-Asp(OCH₂OPropofol)-OH; H-Asn-Asp(OPropofol)-OH;H-Asn-D-Thr(γ-OC(O)OPropofol)-OH; H-Asn-Glu(OPropofol)-OH;H-Asn-OPropofol Hydrochloride; H-Asn-Thr(β-OC(O)OPropofol)-OH;H-Asn-Thr(γ-OC(O)OPropofol)-OH Hydrochloride; H-Asn-Tyr-OPropofol;H-Asp(OCH₂OPropofol)-Arg-OH; H-Asp(OCH₂OPropofol)-Asp-OH;H-Asp(OCH₂OPropofol)-Lys-OH; H-Asp(OCH₂OPropofol)-OH;H-Asp(OCH₂OPropofol)-Ser-OH; H-Asp(OPropofol)-Ala-OH;H-Asp(OPropofol)-Asp-OH; H-Asp(OPropofol)-Gln-OH;H-Asp(OPropofol)-Glu-OH; H-Asp(OPropofol)-Gly-OH;H-Asp(OPropofol)-Ile-OH; H-Asp(OPropofol)-Leu-OH;H-Asp(OPropofol)-Met-OH; H-Asp(OPropofol)-OBzl; H-Asp(OPropofol)-OH;H-Asp(OPropofol)-O-Trityl; H-Asp(OPropofol)-Phe-OH;H-Asp(OPropofol)-Pro-OH; H-Asp(OPropofol)-Ser-OH;H-Asp(OPropofol)-Val-OH; H-Asp-Ala-OPropofol; H-Asp-Asn-OPropofol;H-Asp-Asp(OCH₂OPropofol)-OH; H-Asp-Asp(OPropofol)-OH;H-Asp-OCH₂OPropofol; H-Asp-Phe-OPropofol;H-Asp-Ser(β-OC(O)OPropofol)-OH; H-Asp-Tyr-OPropofol;H-Cys-Asp(OPropofol)-OH; H-Dap(β-NHC(O)OPropofol)-Ala-OH;H-Dap-Ala-OPropofol; H-Dap-Asn-OPropofol; H-Dap-Thr(γ-OC(O)OPropofol)-OHBis-Hydrochloride; H-Dap-Tyr-OPropofol;H-D-Asn-Thr(γ-OC(O)OPropofol)-OH; H-D-Lys-Thr(γ-OC(O)OPropofol)-OHBis-Hydrochloride; H-D-Ser-Thr(γ-OC(O)OPropofol-OH Hydrochloride;H-Gln-Asn-OPropofol; H-Gln-Asp(OCH₂OPropofol)-OH; H-Gln-OPropofolHydrochloride; H-Gln-Phe-OPropofol; H-Glu(OPropofol)-Ala-OH;H-Glu(OPropofol)-Arg-OH; H-Glu(OPropofol)-Asp-OH;H-Glu(OPropofol)-Gln-OH; H-Glu(OPropofol)-Glu-OH;H-Glu(OPropofol)-Gly-OH; H-Glu(OPropofol)-Ile-OH;H-Glu(OPropofol)-Leu-OH; H-Glu(OPropofol)-Lys-OH;H-Glu(OPropofol)-Met-OH; H-Glu(OPropofol)-OBzl; H-Glu(OPropofol)-OH;H-Glu(OPropofol)-Phe-OH; H-Glu(OPropofol)-Ser-OH;H-Glu(OPropofol)-Val-OH; H-Glu-Asp(OCH₂OPropofol)-OH;H-Glu-Phe-OPropofol; H-Glu-Tyr-OPropofol; H-Gly-Asn-OPropofol;H-Gly-Asp(OCH₂OPropofol)-OH; H-Gly-OPropofol Hydrochloride;H-Gly-Phe-OPropofol; H-Gly-Thr(γ-OC(O)OPropofol)-OH;H-Gly-Tyr-OPropofol; H-His-Asp(OCH₂OPropofol)-OH; H-His-OPropofol:H-His-Phe-OPropofol; H-His-Thr(γ-OC(O)OPropofol)-OH Bis-Hydrochloride;H-Leu-Asp(OPropofol)-OH; H-Leu-D-Thr(γ-OC(O)OPropofol)-OH;H-Leu-Glu(OPropofol)-OH; H-Leu-Thr(γ-OC(O)OPropofol)-OH Hydrochloride;H-Lys-Asp(OPropofol)-OH; H-Lys-Cys(β-SC(O)OPropofol)-OH;H-Lys-Glu(OPropofol)-OH; H-Lys-OPropofol Hydrochloride;H-Lys-Ser(β-OC(O)OPropofol)-OH; H-Lys-Thr(β-OC(O)OPropofol)-OH;H-Lys-Thr(γ-OC(O)OPropofol)-OH Bis-Hydrochloride; H-Lys-Tyr-OPropolol;H-Met-Asp(OPropofol)-OH; H-Met-OPropofol; H-Met-Thr(γ-OC(O)OPropofol)-OHHydrochloride; H-NVal-Asp(OPropofol)-OH; H-Om-Asp(OPropofol)-OH;H-Om-Thr(γ-OC(O)OPropofol)-OH Bis-Hydrochloride;H-Phe-Asp(OPropofol)-OH; H-Phe-OPropofol. H-Pro-OPropofol Hydrochloride;H-Pro-Phe-OPropofol; H-Pro-Thr(γ-OC(O)OPropofol)-OH Hydrochloride;H-Pro-Tyr-OPropofol; H-Sar-Asp(OPropofol)-OH; H-Ser-Asn-OPropofol;H-Ser-Asp(OCH₂OPropofol)-OH; H-Ser-Cys(β-SC(O)OPropofol)-OH;H-Ser-D-Thr(γ-OC(O)OPropofol)-OH; H-Ser-OPropofol; H-Ser-Phe-OPropofol;H-Ser-Ser(β-OC(O)OPropofol)-OH; H-Ser-Thr(β-OC(O)OPropofol)-OH;H-Ser-Thr(γ-OC(O)OPropofol)-OH Hydrochloride (19); H-Ser-Tyr-OPropofol;H-Thr-Asp(OCH₂OPropofol)-OH; H-Thr-OPropofol Hydrochloride;H-Thr-Phe-OPropofol; H-Trp-Asp(OCH₂OPropofol)-OH; H-Trp-Phe-OPropofol;H-Tyr-Asn-OPropofol; H-Tyr-Asp(OCH₂OPropofol)-OH;H-Tyr-Asp(OPropofol)-OH; H-Tyr-OPropofol Hydrochloride;H-Tyr-Phe-OPropofol; H-Tyr-Ser(β-OC(O)OPropofol)-OH;H-Val-Ala-OPropofol; H-Val-Asn-OPropofol; H-Val-OCH₂OPropofol;H-Val-OPropofol; H-Val-Phe-OPropofol; H-Val-Ser-OPropofol;H-Val-Thr(β-OC(O)OPropofol)-OH; H-Val-Thr(γ-OC(O)OPropofol)-OHHydrochloride H-Val-Tyr-OPropofol; 2,6-(Diisopropyl)phenylhydroxybutyrate disodium phosphate; 2,6-(Diisopropyl)phenylhydroxyvalerate phosphate disodium salt; H-β-Ala-Asp(OPropofol)-OH;H-β-Ala-Thr(γ-OC(O)OPropofol)-OH Hydrochloride;I-Amino-2-[2,6-(diisopropyl)phenoxycarbonyloxy]ethane;N-(2-Dibutylaminoethyl)-succinamic acid 2,6-diisopropyl-phenyl ester;N-(2-Dibutylaminoethyl)-succinamic acid 2,6-diisopropyl-phenyl esterhydrochloride; N-(2-Diethylamino-ethyl)-succinamic acid2,6-diisopropyl-phenyl ester Hydrochloride;N-(2-Diethylammoethyl)-succinamic acid 2,6-diisopropylphenyl ester;N-(2-Diisopropylaminoethyl)-succinamic acid 2,6-diisopropyl-phenylester; N-(2-Diisopropylamino-ethyl)-succinamic acid2,6-diisopropylphenyl ester Hydrochloride;N-(2-Dimethylamino-ethyl)-succinamic acid 2,6-diisopropyl-phenyl esterHydrochloride; N-(2-Dimethylaminoethyl)-succinamic acid2,6-diisopropyl-phenyl ester; N-(2-Morpholin-4-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester; N-(2-Morpholin-4-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester Hydrochloride;N-(2-Piperidin-1-yl-ethyl)-succinamic acid 2,6-diisopropylphenyl ester;N-(2-Piperidin-1-yl-ethyl)-succinamic acid 2,6-diisopropylphenyl esterhydrochloride; N-(2-Pyrrolidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester; N-(2-Pyrrolidin-1-yl-ethyl)-succinamic acid2,6-diisopropylphenyl ester hydrochloride;O-[t-butoxycarbonyl]-propofol); propofol2-carboxyl-2(S)-fluoropropionate sodium salt; propofol3-(N,N-diethyl)amino-2-(R,S)-fluoropropionate hydrochloride; propofol3-(N-isopropyl)amino-2-(R,S)-2-monofluoromethylpropionatemethanesulfonate; propofol3-(N-isopropyl)amino-2(R,S)-2-monofluoromethylpropionatemethanesulfonate; propofol 3-(pyrrolidin-1-yl)-2-(S)-trifluoromethylpropionate hydrochloride; propofol3-(pyrrolidin-1-yl)-2(S)-trifluoromethylpropionate hydrochloride;propofol 3-carboxyl-2(R)-fluorobutyrate sodium salt; propofol3-N-isopropylamino-2-(R,S)-fluoropropionate hydrochloride; propofol3-N-methyl-N-cyclohexylamino-2-(R,S)-fluoropropionate hydrochloride;propofol 3-N-methyl-N-cyclohexylamino-2(R,S)-fluoropropionatehydrochloride; propofol 3-phosphoryl-2-(R,S-fluoropropionate zinc salt;propofol 4-(aziridin-1-yl)-2-(S)-2-fluorobutyrate hydrochloride;propofol 4-(N,N-dimethyl)amino-2-(R)-2-trifluoromethylbutyratehydrochloride; propofol 4-(N,N-dimethyl)amino-2-(R)-fluorobutyratehydrochloride; propofol4-(N,N-dimethyl)amino-2-(R)-trifluoromethylbutyrate hydrochloride;propofol 4-(N,N-dimethyl)amino-2-(R,S)-fluorobutyrate hydrochloride;propofol 4-(N-cyclopropyl-N-methyl)amino-2-(R)-difluoromethylbutyratehydrochloride; propofol4-(N-methyl-N-benzyl)amino-2-(R,S)-trifluoromethylbutyratehydrochloride; propofol4-(N-methyl-N-ethyl)amino-2-(R,S)-2-fluorobutyrate hydrochloride;propofol 4-(N-methyl-N-isopropyl)amino-2-(R,S)-fluorobutyratemethanesulfonate; propofol 4-(pyrrolidin-1-yl)-2-(R)-2-fluorobutyratehydrochloride; propofol 4-carboxyl-2-(R)-2-trifluoromethylvaleratelithium salt; propofol 4-carboxyl-2(R)-fluorobutyrate sodium salt;propofol 4-carboxyl-2-(R,S)-difluoromethylvalerate potassium salt;propofol 4-carboxyl-2(R,S)-fluorovalerate sodium salt; propofol4-carboxyl-2(S)-fluorovalerate potassium salt; propofol4-carboxyl-2-(S)-fluorovalerate potassium salt; propofol4-carboxyl-2-(S)-trifluoromethylbutyrate ammonium salt; propofol4-N-(aziridin-1-yl)-2(S)-2-fluorobutyrate hydrochloride; propofol4-N-methyl-N-benzylamino-2-(R)-fluorobutyrate hydrochloride; propofol4-phosphoryl-2-(R)-fluorobutyrate disodium salt; propofol4-phosphoryl-2-(R,S)-fluorobutyrate calcium salt; propofol5-(N-methyl-N-benzyl)amino-2-(S)-2-fluorovalerate hydrochloride;propofol 5-carboxyl-2(R,S)-difluoromethylvalerate potassium salt;propofol 5-N-cyclopentylamino-2,2-difluorovalerate hydrochloride,propofol 5-phosphoryl-2-(S)-fluorovalerate zinc salt; propofol6-(N,N-dimethyl)amino-2(R)-fluorovalerate hydrochloride; PropofolHemisuccinate; propofol hydroxybutyrate; propofol hydroxyvalerate;propofol δ-(N,N-dimethyl)amino-2-(R)-fluorovalerate hydrochloride;propofol-2-(R)-fluoropropionate monoester sodium salt;propofol-2-(R,S)-fluorobutyrate monoester sodium salt;propofol-2-(R,S)-fluoropentanoate monoester sodium salt;(S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acidmesylate; Sodium 4-(2,6-Diisopropylphenoxy)-4-Oxobutyl Phosphate;2-(2,6-diisopropylphenoxy)-tetrahydropyran-6-yl dihydrogen phosphatearginine; tri[propofol3-phosphoryl-2-(R,S)-2-monofluoromethylpropionate] dialuminum salt;tri[propofol 8-carboxyl-2-(R,S)-monofluoromethylpelargonate] aluminumsalt; Succinic Acid Mono-Propofol Ester; Propofol to Maltotrionic Acid;Propofol to Glucuronic Acid; Propofol to Gluconic Acid; Propofol toModified Glucose; BOC-protected 1-deoxy-1-hydrazinoglucitol;2-amino-3-methyl-3-(2,6-diisopropyl-phenoxycarbonyloxy)-propanoic acid;2-amino-3-(2,6-diisopropyl-phenoxycarbonyloxy)-propanoic acid;1-(2,6-diisopropylphenoxy)ethyl dihydrogen phosphate; Mono(propofol)phosphate; Di(propofol) phosphate; Carboxylic hemiesters of propofol;hemisuccinate ester of propofol; hemiglutarate ester of propofol;hemiadipate ester of propofol.; (2′,6′-Diisopropylphenyl4-(2-trimethylammoniumethyloxy) phosphonobutyrate); (2′,6′-Diisopropylphenyl 3-ortho-(O-trimethylammoniumethylphosphonooxy)Ipropionate}; (4-(2,6-diisopropylphenoxy)-4-oxobutanoyl)glycine;4-(4-(2,6-diisopropylphenoxy)-4-oxobutanamido)butanoic acid; HX0507;HX0969w; HX0892; HX0891; propofol methoxymethylphosphonic prodrug;propofol hemiglutarate; propofol hemiadipate; monopropofol phosphate;dipropofol phosphate;1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)-3-(dimethylcarbamoyl)pyridiniummesylate;1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)-3-(methylcarbamoyl)pyridiniummesylate;3-carbamoyl-1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)pyridiniummesylate;1-(((2,6-diisopropylphenoxy)carbonyloxy)methyl)-3-(methylcarbamoyl)pyridiniumiodide;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-1-iummethanesulfonate;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-1-iumiodide;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methoxycarbonyl)pyridin-1-iumiodide;3-carboxy-1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)pyridin-1-iumiodide;2-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N,N,N-trimethylethan-1-aminiumiodide;2-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N,N-dimethylethan-1-aminiumchloride;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(hydroxycarbamoyl)pyridin-1-iumiodide;3-(((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)carbamoyl)-1-methylpyridin-1-iumiodide;1-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-N,N-dimethylmethanaminiumiodide;2-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-N,N-dimethylethan-1-aminiumiodide;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-4-formyl-3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-1-iumiodide;3-((2,6-diisopropylphenoxy)carbonyl)-1-((((2,6-diisopropylphenoxy)carbony-1)oxy)methyl)pyridin-1-iummethanesulfonate;2-(((2,6-diisopropylphenoxy)carbonyl)oxy)-N,N,N-trimethylethan-1-aminiummethanesulfonate;3-carbamoyl-1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methy)pyridin-1-iumbromide;3-carbamoyl-1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)pyridin-1-iumchloride;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methylcarbamoyl)pyridin-1-iumtetrafluoroborate;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methylcarbamoyl)pyridin-1-iumnitrate;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methylcarbamoyl)pyridin-1-iumchloride;1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)-3-(methoxycarbonyl)pyridin-1-iummethanesulfonate; or3-carboxy-1-((((2,6-diisopropylphenoxy)carbonyl)oxy)methyl)pyridin-1-iummethanesulfonate.

In some embodiments, the administering is oral.

In some embodiments, the administering is peroral.

In other embodiments, the administering is subcutaneous.

In other embodiments, the administering is intramuscular.

In other embodiments, the administering is intravenous.

In other embodiments, the administering is rectal.

In the methods of the disclosure, the patient is administered aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof.

In some embodiments of the methods of the disclosure, the patient isadministered an effective amount of fospropofol.

In other embodiments, the patient is administered an effective amount ofa pharmaceutically acceptable salt of fospropofol.

In some embodiments of the methods, the pharmaceutically acceptable saltof fospropofol is the disodium salt, i.e., fospropofol disodium, havingthe structure:

In some embodiments, the patient is administered an effective amount ofa mixture of fospropofol and a pharmaceutically acceptable salt thereof.Thus, in some embodiments, the patient is administered an effectiveamount of fospropofol and fospropofol disodium.

In other embodiments, the patient is administered an effective amount ofa mixture of pharmaceutically acceptable salts. In some embodiments, thepatient is administered an effective amount of a mixture of fospropofoldisodium and a second pharmaceutically acceptable fospropofol salt.

In some aspects of the methods of the disclosure, the patient isadministered an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isan amount of 50-4800 mg (on a fospropofol basis), for example, an amountthat is about (i.e., the specified number±10%) any one of 50 mg, 100 mg,150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg,600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg. 900 mg, 950 mg, 1000 mg,1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg,1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg,1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg,2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg,2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg,2050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg,3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg,3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg,4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg,4650 mg, 4700 mg, 4750 mg, or 4800 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isan amount of 50-1000 mg (on a fospropofol basis), for example, an amountthat is about (i.e., the specified number±10%) any one of 50 mg, 100 mg,150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg,600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isan amount of 50-750 mg (on a fospropofol basis), for example, an amountthat is about (i.e., the specified number±10%) any one of 50 mg, 75 mg,100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg,325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg,550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, or 750mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isan amount of 75-1500 mg (on a fospropofol basis), for example, an amountthat is about (i.e., the specified number±10%) any one of 75 mg, 150 mg,225 mg, 300 mg, 375 mg, 450 mg, 525 mg, 600 mg, 675 mg, 750 mg, 825 mg,900 mg, 975 mg, 1050 mg, 1125 mg, 1200 mg, 1275 mg, 1350 mg, 1425 mg, or1500 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is100-4800 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 100 mg, 150 mg, 200mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg,1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg,1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg,1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg,2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg,2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg,3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg,3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg,3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg,4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg,4700 mg, 4750 mg, or 4800 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is100-3600 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 100 mg, 150 mg, 200mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg,1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg,1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg,1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg,2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg,2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg,3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg,3500 mg, 3550 mg, or 3600 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is100-3200 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 100 mg, 150 mg, 200mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg,1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg,1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg,1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg,2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg,2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg,3100 mg, 3150 mg, or 3200 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-2400 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg. 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg,2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg,or 2400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-2300 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg,2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, or 2300 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-2200 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg,2000 mg, 2050 mg, 2100 mg, 2150 mg, or 2200 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-2100 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg,2000 mg, 2050 mg, or 2100 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-2000 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg. 1850 mg, 1900 mg, 1950 mg,or 2000 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1900 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, or 1900 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1800 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, or 1800 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1700 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, or 1700 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1600 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg. 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,or 1600 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1600 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,or 1600 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1500 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, or 1500 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1400 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1300 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg. 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, or 1300 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1200 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg. 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg,or 1200 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1100 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, or 1100 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-1000 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±110%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-900 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, or 900 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-800 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, or 800 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-700 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg. 600 mg, 650 mg, or 700 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-600 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-500 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, or 500 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-400 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, 300mg, 350 mg, or 400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is200-300 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 200 mg, 250 mg, or 300mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-2400 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, or 2400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-2000 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-1600 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-1200 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-1200 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-1000 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg. 800 mg, 850 mg, 900 mg, 950mg, or 1000 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-800 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400-600 ng (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 400 mg, 450 mg, 500mg, 550 mg, or 600 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is600-1200 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 600 mg, 650 mg, 700mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg,1150 mg, or 1200 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is800-1200 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 800 mg, 850 mg, 900mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is1000-2000 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 1000 mg, 1050 mg, 1100mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg. 1800 mg, 1850 mg, 1900mg, 1950 mg, or 2000 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is1000-1600 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 1000 mg, 1050 mg, 1100mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500mg, 1550 mg, or 1600 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is1200-2000 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 1200 mg, 1250 mg, 1300mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is1200-1800 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 1200 mg, 1250 mg, 1300mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700mg, 1750 mg, or 1800 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is1600-2400 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 1600 mg, 1650 mg, 1700mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, or 2400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is1800-2400 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 1800 mg, 1850 mg, 1900mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300mg, 2350 mg, or 2400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is2000-2400 mg (on a fospropofol basis), for example, an amount that isabout (i.e., the specified number±10%) any one of 2000 mg, 2050 mg, 2100mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, or 2400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is400 mg (on a fospropofol basis).

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is500 mg (on a fospropofol basis).

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is600 mg (on a fospropofol basis).

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is700 mg (on a fospropofol basis).

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is800 mg (on a fospropofol basis).

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is900 mg (on a fospropofol basis).

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, is1000 mg (on a fospropofol basis).

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isabout 1 mg/kg to about 80 mg/kg, for example, an amount that is about(i.e., the specified number±10%) any one of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg,12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32 mg/kg, 33mg/kg, 34 mg/kg, 35 mg/kg, 36 mg/kg, 37 mg/kg, 38 mg/kg, 39 mg/kg, 40mg/kg, 41 mg/kg, 42 mg/kg, 43 mg/kg, 44 mg/kg, 45 mg/kg, 46 mg/kg, 47mg/kg, 48 mg/kg, 49 mg/kg, 50 mg/kg, 51 mg/kg, 52 mg/kg, 53 mg/kg, 54mg/kg, 55 mg/kg, 56 mg/kg, 57 mg/kg, 58 mg/kg, 59 mg/kg, 60 mg/kg, 61mg/kg, 62 mg/kg, 63 mg/kg, 64 mg/kg, 65 mg/kg, 66 mg/kg, 67 mg/kg, 68mg/kg, 69 mg/kg, 70 mg/kg, 71 mg/kg, 72 mg/kg, 73 mg/kg, 74 mg/kg, 75mg/kg, 76 mg/kg, 77 mg/kg, 78 mg/kg, 79 mg/kg, or 80 mg/kg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isabout 7 mg/kg to 15 mg/kg, for example, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9,9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2,10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4,11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6,12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8,13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, or15.0 mg/kg.

In the methods of the disclosure, an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in one or more doses.

In some embodiments of the disclosed methods, an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, is administered in one dose.

In some embodiments of the disclosed methods, an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, is administered in more than one dose.

In some embodiments of the disclosed methods, an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, is administered in two or more doses.

In some embodiments, an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in two doses.

In other embodiments, an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in more than two doses.

In other embodiments, an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in three doses.

In other embodiments, an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in more than three doses.

In other embodiments, an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in four doses.

In other embodiments, an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in more than four doses.

In some embodiments of the disclosed methods in which an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 5-120 minutes, for example, a time interval that is about(i.e., the specified number±10%) any one of 5 minutes, 10 minutes, 15minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes,105 minutes, 110 minutes, 115 minutes, or 120 minutes.

In some embodiments in which the dose is administered intravenously, thetime interval between administration of the first dose andadministration of the second dose is about 5-15 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of5 minutes, 10 minutes, or 15 minutes. In other embodiments of thedisclosed methods in which the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered in two or more doses, two doses, or more than two doses,the time interval between administration of the first dose andadministration of the second dose is about 5-105 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes,35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes,65 minutes, 70 minutes, 75 minutes, minutes, 85 minutes, 90 minutes, 95minutes, or 105 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 5-30 minutes, for example, a time interval that is about (i.e.,the specified number±10%) any one of 5 minutes, 10 minutes, 15 minutes,20 minutes, or 30 minutes.

In some embodiments in which the dose is administered perorally, thetime interval between administration of the first dose andadministration of the second dose is about 5-30 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes. In otherembodiments of the disclosed methods in which the effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, is administered in two or more doses, two doses, ormore than two doses, the time interval between administration of thefirst dose and administration of the second dose is about 30 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 30-90 minutes, for example, a time interval that is about(i.e., the specified number±10%) any one of 30 minutes, 45 minutes, 60minutes, 75 minutes, or 90 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 30-75 minutes, for example, a time interval that is about(i.e., the specified number±10%) any one of 30 minutes, 45 minutes, 60minutes, or 75 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 30-60 minutes, for example, a time interval that is about(i.e., the specified number±10%) any one of 30 minutes, 45 minutes, or60 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 30-45 minutes, for example, a time interval that is about(i.e., the specified number±10%) any one of 30 minutes, or 45 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 1-24 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 1 hour, 2 hours, 2.5 hours, 3hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours,13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, 16 hours, 16.5hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours,20 hours, 20.5 hours, 21 hours, 21.5 hours, 22 hours, 22.5 hours, 23hours, 23.5 hours, or 24 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 1-4 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 1 hour, 2 hours, 2.5 hours, 3hours, 3.5 hours, or 4 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 4-8 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 4 hours, 4.5 hours, 5 hours, 5.5hours, 6 hours, 6.5 hours, 7 hours. 7.5 hours, or 8 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 8-12 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 8 hours, 8.5 hours, 9 hours, 9.5hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, or 12 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 12-16 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 12 hours, 12.5 hours, 13 hours.13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, or 16 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 16-20 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 16 hours, 16.5 hours, 17 hours,17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours, or 20 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 20-24 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 20 hours, 20.5 hours, 21 hours,21.5 hours, 22 hours, 22.5 hours, 23 hours, 23.5 hours, or 24 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 24-48 hours, for example, a time interval that is about (i.e.,the specified number±10%) any one of 24 hours, 24.5 hours, 25 hours.25.5 hours, 26 hours, 26.5 hours, 27 hours, 27.5 hours, or 28 hours,28.5 hours, 29 hours, 29.5 hours, 30 hours, 30.5 hours, 31 hours, 31.5hours, 32 hours, 32.5 hours, 33 hours, 33.5 hours, 34 hours, 34.5 hours,35 hours, 35.5 hours, 36 hours, 36.5 hours, 37 hours, 37.5 hours, 38hours, 38.5 hours, 39 hours, 39.5 hours, 40 hours, 40.5 hours, 41 hours,41.5 hours, 42 hours, 42.5 hours, 43 hours, 43.5 hours, 44 hours, 44.5hours, 45 hours, 45.5 hours, 46 hours, 46.5 hours, 47 hours, 47.5 hours,or 48 hours.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, or 100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 20-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 30-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, or 100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 40-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 50-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 60-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 70-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 80-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 80%, 85%, 90%, 95%, or 100%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 90-100% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 90%, 95%, or 100%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-90% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, or 90%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-80% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, or 80%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-70% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, or70%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-60% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, or 60%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-50% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, or 50%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-40% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, 30%, 35%, or 40%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-30% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, 20%, 25%, or 30%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides 10-20% (byweight on a fospropofol basis) of the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,for example, a percentage that is about (i.e., the specified number±10%)one of 10%, 15%, or 20%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the first dose provides a percentagethat is about (i.e., the specified number±10%) one of 10%, 15%, 20%,25%, 30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%, 90%,95%, or 100% of the effective amount of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 5-120 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes,35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes,65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes,95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes or 120minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 5-105 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes,35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes,65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes,95 minutes, 100 minutes, or 105 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in two or more doses,two doses, or more than two doses, the time interval betweenadministration of the first dose and administration of the second doseis about 30 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 30-90 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of30 minutes, 45 minutes, 60 minutes, 75 minutes, or 90 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 30-75 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of30 minutes, 45 minutes, 60 minutes, or 75 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 30-60 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of30 minutes, 45 minutes, or 60 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 30-45 minutes, for example, atime interval that is about (i.e., the specified number±10%) any one of30 minutes, or 45 minutes.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 1-24 hours, for example, atime interval that is about (i.e., the specified number±10%) any one of1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5hours, 5.5 hours, 6 hours, 6.5 hours. 7 hours, 7.5 hours, 8 hours, 8.5hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours,12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15hours, 15.5 hours, 16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours,18.5 hours, 19 hours, 19.5 hours, 20 hours, 20.5 hours, 21 hours, 21.5hours, 22 hours, 22.5 hours, 23 hours, 23.5 hours, or 24 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 1-4 hours, for example, a timeinterval that is about (i.e., the specified number±10%) any one of 1hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 4-8 hours, for example, a timeinterval that is about (i.e., the specified number±10%) any one of 4hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5hours, or 8 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 8-12 hours, for example, atime interval that is about (i.e., the specified number±10%) any one of8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours,11.5 hours, or 12 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 12-16 hours, for example, atime interval that is about (i.e., the specified number±10%) any one of12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15hours, 15.5 hours, or 16 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 16-20 hours, for example, atime interval that is about (i.e., the specified number±10%) any one of16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19hours, 19.5 hours, or 20 hours.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the time interval between administration of the second dose andadministration of the third dose is about 20-24 hours, for example, atime interval that is about (i.e., the specified number±10%) any one of20 hours, 20.5 hours, 21 hours, 21.5 hours, 22 hours, 22.5 hours, 23hours, 23.5 hours, or 24 hours.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 10-80% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 10%, 15%, 20%, 25%,30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 20-80% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 20%. 25%, 30%, 35%40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 30-80% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 30%, 35% 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, or 80%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 40-80% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, or 80%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 50-80% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 50%, 55%, 60%, 65%,70%, 75%, or 80%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 60-80% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 60%, 65%, 70%, 75%,or 80%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 70-80% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 70%, 75%, 80%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 10-70% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 10%, 15%, 20%, 25%,30%, 35% 40%, 45%, 50%, 55%, 60%, 65%, or 70%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 10-60% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 10%, 15%, 20%, 25%,30%, 35% 40%, 45%, 50%, 55%, or 60%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 10-50% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 10%, 15%, 20%, 25%,30%, 35% 40%, 45%, or 50%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 10-40% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 10%, 15%, 20%, 25%,30%, 35%, or 40%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 10-30% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 10%, 15%, 20%, 25%,or 30%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides 10-20% (by weight on a fospropofol basis)of the effective amount of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, for example, a percentage thatis about (i.e., the specified number±10%) any one of 10%, 15%, or 20%.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the first dose provides a percentage that is about (i.e., thespecified number±10%) any one of 10%, 15%, 20%, 25%. 30%, 35% 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, or 80% (by weight on a fospropofol basis)of the effective amount of fospropofol, or a pharmaceutically acceptablesalt thereof.

In some embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the second dose provides 10-60% (by weight on a fospropofolbasis) of the effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, for example, apercentage that is about (i.e., the specified number±10%) any one of10%, 15%, 20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, or 60%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the second dose provides 20-60% (by weight on a fospropofolbasis) of the effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, for example, apercentage that is about (i.e., the specified number±10%) any one of20%, 25%, 30%, 35% 40%, 45%, 50%, 55%, or 60%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the second dose provides 30-60% (by weight on a fospropofolbasis) of the effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, for example, apercentage that is about (i.e., the specified number±10%) any one of30%, 35% 40%, 45%, 50%, 55%, or 60%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the second dose provides 40-60% (by weight on a fospropofolbasis) of the effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, for example, apercentage that is about (i.e., the specified number±10%) any one of40%, 45%, 50%, 55%, or 60%.

In other embodiments of the disclosed methods in which the effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, is administered in more than twodoses, the second dose provides 50-60% (by weight on a fospropofolbasis) of the effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, for example, apercentage that is about (i.e., the specified number±10%) any one of50%, 55%, or 60%.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma Cmax or mean Cmax of propofol of at least 200-4000 ng/mL, forexample, a Cmax or mean Cmax that is about (i.e., the specifiednumber±10%) any one of 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL,750 ng/mL, 800 ng/mL, 850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050ng/mL, 1100 ng/mL, 1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350ng/mL, 1400 ng/mL, 1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650ng/mL, 1700 ng/mL, 1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 2000ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900ng/mL, 2950 ng/mL, 3000 ng/mL, 3050 ng/mL, 3100 ng/mL, 3150 ng/mL, 3200ng/mL, 3250 ng/mL, 3300 ng/mL, 3350 ng/mL, 3400 ng/mL, 3450 ng/mL, 3500ng/mL, 3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800ng/mL, 3850 ng/mL, 3900 ng/mL, 3950 ng/mL, or 4000 ng/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma Cmax or mean Cmax of propofol of at least 200-1600 ng/mL, forexample, a Cmax or mean Cmax that is about (i.e., the specifiednumber±10%) any one of 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL,750 ng/mL, 800 ng/mL, 850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050ng/mL, 1100 ng/mL, 1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350ng/mL, 1400 ng/mL, 1450 ng/mL, 1500 ng/mL, 1550 ng/mL, or 1600 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofat least 200-1200 ng/mL, for example, a Cmax or mean Cmax that is about(i.e., the specified number±10%) any one of 200 ng/mL, 250 ng/mL, 300ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, 600 ng/mL,650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900 ng/mL, 950ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, or 1200 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofat least 200-1000 ng/mL, for example, a Cmax or mean Cmax that is about(i.e., the specified number±10%) any one of 200 ng/mL, 250 ng/mL, 300ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, 600 ng/mL,650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900 ng/mL, 950ng/mL, or 1000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofat least 200-800 ng/mL, for example, a Cmax or mean Cmax that is about(i.e., the specified number±10%) any one of 200 ng/mL, 250 ng/mL, 300ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, 600 ng/mL,650 ng/mL, 700 ng/mL, 750 ng/mL, or 800 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofat least 200-600 ng/mL, for example, a Cmax or mean Cmax that is about(i.e., the specified number±10%) any one of 200 ng/mL, 250 ng/mL, 300ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, or 600ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofat least 200-400 ng/mL, for example, a Cmax or mean Cmax that is about(i.e., the specified number±10%) any one of 200 ng/mL, 250 ng/mL, 300ng/mL, 350 ng/mL, or 400 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofat least 50-500 ng/mL, for example, a Cmax or mean Cmax that is about(i.e., the specified number±10%) any one of 50 ng/mL, 100 ng/mL, 150ng/mL, 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL,or 500 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofno greater than 5000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofno greater than 4000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofno greater than 3000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofno greater than 2000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of propofol ofno greater than 1600 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 1200 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 1000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 800 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 600 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 500 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 400 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 200 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax of propofolof no greater than 100 ng/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma Cmax or mean Cmax of fospropofol of at least 800-18000 ng/mL, forexample, a Cmax or mean Cmax that is about (i.e., the specifiednumber±10%) any one of 800 ng/mL, 850 ng/mL, 900 ng/mL, 950 ng/mL, 1000ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900ng/mL, 1950 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL, 2200ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL, 2500ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL, 2800ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL, 3550ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850ng/mL, 3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL, 4150ng/mL, 4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL, 4450ng/mL, 4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL, 4750ng/mL, 4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL, 5050ng/mL, 5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL, 5350ng/mL, 5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL, 5650ng/mL, 5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL, 5950ng/mL, 6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL, 6250ng/mL, 6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL, 6550ng/mL, 6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL, 6850ng/mL, 6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL, 7150ng/mL, 7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL, 7450ng/mL, 7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL, 7750ng/mL, 7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL, 8050ng/mL, 8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL, 8350ng/mL, 8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL, 8650ng/mL, 8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL, 8950ng/mL, 9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL, 9250ng/mL, 9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL, 9550ng/mL, 9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL, 9950ng/mL, 9900 ng/mL, 9950 ng/mL, 10000 ng/mL, 10050 ng/mL, 10100 ng/mL,10150 ng/mL, 10200 ng/mL, 10250 ng/mL, 10300 ng/mL, 10350 ng/mL, 10400ng/mL, 10450 ng/mL, 10500 ng/mL, 10550 ng/mL, 10600 ng/mL, 10650 ng/mL,10700 ng/mL, 10750 ng/mL, 1000 ng/mL, 101050 ng/mL, 10900 ng/mL, 10950ng/mL, 11000 ng/mL, 11050 ng/mL, 11100 ng/mL, 11150 ng/mL, 11200 ng/mL,11250 ng/mL, 11300 ng/mL, 11350 ng/mL, 11400 ng/mL, 11450 ng/mL, 11500ng/mL, 11550 ng/mL, 11600 ng/mL, 11650 ng/mL, 11700 ng/mL, 11750 ng/mL,1100 ng/mL, 111150 ng/mL, 11900 ng/mL, 11950 ng/mL, 12000 ng/mL, 12050ng/mL, 12100 ng/mL, 12150 ng/mL, 12200 ng/mL, 12250 ng/mL, 12300 ng/mL,12350 ng/mL, 12400 ng/mL, 12450 ng/mL, 12500 ng/mL, 12550 ng/mL, 12600ng/mL, 12650 ng/mL, 12700 ng/mL, 12750 ng/mL, 1200 ng/mL, 121250 ng/mL,12900 ng/mL, 12950 ng/mL, 13000 ng/mL, 13050 ng/mL, 13100 ng/mL, 13150ng/mL, 13200 ng/mL, 13250 ng/mL, 13300 ng/mL, 13350 ng/mL, 13400 ng/mL,13450 ng/mL, 13500 ng/mL, 13550 ng/mL, 13600 ng/mL, 13650 ng/mL, 13700ng/mL, 13750 ng/mL, 1300 ng/mL, 131350 ng/mL, 13900 ng/mL, 13950 ng/mL,14000 ng/mL, 14050 ng/mL, 14100 ng/mL, 14150 ng/mL, 14200 ng/mL, 14250ng/mL, 14300 ng/mL, 14350 ng/mL, 14400 ng/mL, 14450 ng/mL, 14500 ng/mL,14550 ng/mL, 14600 ng/mL, 14650 ng/mL, 14700 ng/mL, 14750 ng/mL, 1400ng/mL, 141450 ng/mL, 14900 ng/mL, 14950 ng/mL, 15000 ng/mL, 15050 ng/mL,15100 ng/mL, 15150 ng/mL, 15200 ng/mL, 15250 ng/mL, 15300 ng/mL, 15350ng/mL, 15400 ng/mL, 15450 ng/mL, 15500 ng/mL, 15550 ng/mL, 15600 ng/mL,15650 ng/mL, 15700 ng/mL, 15750 ng/mL, 1500 ng/mL, 151550 ng/mL, 15900ng/mL, 15950 ng/mL, 16000 ng/mL, 16050 ng/mL, 16100 ng/mL, 16150 ng/mL,16200 ng/mL, 162550 ng/mL, 16300 ng/mL, 16350 ng/mL, 16400 ng/mL, 16450ng/mL, 16500 ng/mL, 16550 ng/mL, 16600 ng/mL, 16650 ng/mL, 16700 ng/mL,16750 ng/mL, 1600 ng/mL, 161650 ng/mL, 16900 ng/mL, 16950 ng/mL, 17000ng/mL, 17050 ng/mL, 17100 ng/mL, 17150 ng/mL, 17200 ng/mL, 17250 ng/mL,17300 ng/mL, 17350 ng/mL, 17400 ng/mL, 17450 ng/mL, 17500 ng/mL, 17550ng/mL, 17600 ng/mL, 17650 ng/mL, 17700 ng/mL, 17750 ng/mL, 1700 ng/mL,171750 ng/mL, 17900 ng/mL, 17950 ng/mL, or 18000 ng/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma Cmax or mean Cmax of fospropofol of at least 2000-10000 ng/mL,for example, a Cmax or mean Cmax that is about (i.e., the specifiednumber±10%) any one of 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL,2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL,2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL,2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL,3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL,3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL,4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL,4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL,4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL,5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL,5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL,5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL,5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL,6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL,6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL,6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL,7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL,7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL,7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL,8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL,8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL,8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL,8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL,9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL,9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL,9950 ng/mL, 9900 ng/mL, 9950 ng/mL, or 10000 ng/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma Cmax or mean Cmax of fospropofol that is a value that is 80% to125% of (or bioequivalent to) 800-18000 ng/mL, for example, a Cmax ormean Cmax that is a value that is 80% to 125% of (or bioequivalent to)any one of 800 ng/mL, 850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050ng/mL, 1100 ng/mL, 1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350ng/mL, 1400 ng/mL, 1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650ng/mL, 1700 ng/mL, 1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 1950ng/mL, 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900ng/mL, 3950 ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL, 4150 ng/mL, 4200ng/mL, 4250 ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL, 4450 ng/mL, 4500ng/mL, 4550 ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL, 4750 ng/mL, 4800ng/mL, 4850 ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL, 5050 ng/mL, 5100ng/mL, 5150 ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL, 5350 ng/mL, 5400ng/mL, 5450 ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL, 5650 ng/mL, 5700ng/mL, 5750 ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL, 5950 ng/mL, 6000ng/mL, 6050 ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL, 6250 ng/mL, 6300ng/mL, 6350 ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL, 6550 ng/mL, 6600ng/mL, 6650 ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL, 6850 ng/mL, 6900ng/mL, 6950 ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL, 7150 ng/mL, 7200ng/mL, 7250 ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL, 7450 ng/mL, 7500ng/mL, 7550 ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL, 7750 ng/mL, 7800ng/mL, 7850 ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL, 8050 ng/mL, 8100ng/mL, 8150 ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL, 8350 ng/mL, 8400ng/mL, 8450 ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL, 8650 ng/mL, 8700ng/mL, 8750 ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL, 8950 ng/mL, 9000ng/mL, 9050 ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL, 9250 ng/mL, 9300ng/mL, 9350 ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL, 9550 ng/mL, 9600ng/mL, 9650 ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL, 9950 ng/mL, 9900ng/mL, 9950 ng/mL, 10000 ng/mL, 10050 ng/mL, 10100 ng/mL, 10150 ng/mL,10200 ng/mL, 10250 ng/mL, 10300 ng/mL, 10350 ng/mL, 10400 ng/mL, 10450ng/mL, 10500 ng/mL, 10550 ng/mL, 10600 ng/mL, 10650 ng/mL, 10700 ng/mL,10750 ng/mL, 1000 ng/mL, 101050 ng/mL, 10900 ng/mL, 10950 ng/mL, 11000ng/mL, 11050 ng/mL, 11100 ng/mL, 11150 ng/mL, 11200 ng/mL, 11250 ng/mL,11300 ng/mL, 11350 ng/mL, 11400 ng/mL, 11450 ng/mL, 11500 ng/mL, 11550ng/mL, 11600 ng/mL, 11650 ng/mL, 11700 ng/mL, 11750 ng/mL, 1100 ng/mL,111150 ng/mL, 11900 ng/mL, 11950 ng/mL, 12000 ng/mL, 12050 ng/mL, 12100ng/mL, 12150 ng/mL, 12200 ng/mL, 12250 ng/mL, 12300 ng/mL, 12350 ng/mL,12400 ng/mL, 12450 ng/mL, 12500 ng/mL, 12550 ng/mL, 12600 ng/mL, 12650ng/mL, 12700 ng/mL, 12750 ng/mL, 1200 ng/mL, 121250 ng/mL, 12900 ng/mL,12950 ng/mL, 13000 ng/mL, 13050 ng/mL, 13100 ng/mL, 13150 ng/mL, 13200ng/mL, 13250 ng/mL, 13300 ng/mL, 13350 ng/mL, 13400 ng/mL, 13450 ng/mL,13500 ng/mL, 13550 ng/mL, 13600 ng/mL, 13650 ng/mL, 13700 ng/mL, 13750ng/mL, 1300 ng/mL, 131350 ng/mL, 13900 ng/mL, 13950 ng/mL, 14000 ng/mL,14050 ng/mL, 14100 ng/mL, 14150 ng/mL, 14200 ng/mL, 14250 ng/mL, 14300ng/mL, 14350 ng/mL, 14400 ng/mL, 14450 ng/mL, 14500 ng/mL, 14550 ng/mL,14600 ng/mL, 14650 ng/mL, 14700 ng/mL, 14750 ng/mL, 1400 ng/mL, 141450ng/mL, 14900 ng/mL, 14950 ng/mL, 15000 ng/mL, 15050 ng/mL, 15100 ng/mL,15150 ng/mL, 15200 ng/mL, 15250 ng/mL, 15300 ng/mL, 15350 ng/mL, 15400ng/mL, 15450 ng/mL, 15500 ng/mL, 15550 ng/mL, 15600 ng/mL, 15650 ng/mL,15700 ng/mL, 15750 ng/mL, 1500 ng/mL, 151550 ng/mL, 15900 ng/mL, 15950ng/mL, 16000 ng/mL, 16050 ng/mL, 16100 ng/mL, 16150 ng/mL, 16200 ng/mL,16250 ng/mL, 16300 ng/mL, 16350 ng/mL, 16400 ng/mL, 16450 ng/mL, 16500ng/mL, 16550 ng/mL, 16600 ng/mL, 16650 ng/mL, 16700 ng/mL, 16750 ng/mL,1600 ng/mL, 161650 ng/mL, 16900 ng/mL, 16950 ng/mL, 17000 ng/mL, 17050ng/mL, 17100 ng/mL, 17150 ng/mL, 17200 ng/mL, 17250 ng/mL, 17300 ng/mL,17350 ng/mL, 17400 ng/mL, 17450 ng/mL, 17500 ng/mL, 17550 ng/mL, 17600ng/mL, 17650 ng/mL, 17700 ng/mL, 17750 ng/mL, 1700 ng/mL, 171750 ng/mL,17900 ng/mL, 17950 ng/mL, or 18000 ng/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma Cmax or mean Cmax of fospropofol that is a value that is 80% to125% of (or bioequivalent to) 2000-10000 ng/mL, for example, a Cmax ormean Cmax that is a value that is 80% to 125% of (or bioequivalent to)any one of 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL,2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL,2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL,2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL, 3550 ng/mL,3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL,3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL, 4150 ng/mL,4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL, 4450 ng/mL,4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL, 4750 ng/mL,4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL, 5050 ng/mL,5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL, 5350 ng/mL,5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL, 5650 ng/mL,5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL, 5950 ng/mL,6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL, 6250 ng/mL,6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL, 6550 ng/mL,6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL, 6850 ng/mL,6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL, 7150 ng/mL,7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL, 7450 ng/mL,7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL, 7750 ng/mL,7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL, 8050 ng/mL,8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL, 8350 ng/mL,8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL, 8650 ng/mL,8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL, 8950 ng/mL,9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL, 9250 ng/mL,9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL, 9550 ng/mL,9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL, 9950 ng/mL,9900 ng/mL, 9950 ng/mL, or 10000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no greater than 15000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no greater than 14000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no greater than 13000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no greater than 12000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no greater than 11000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 10000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 9000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 8000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 7000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 6000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 5000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 4000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 3000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no greater than 2000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 14000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 13000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 12000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 11000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 10000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 9000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 8000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 7000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 6000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 5000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 4000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 3000 ng/mL.

In other embodiments, administering an effective amount of fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,in one or more doses results in a plasma Cmax or mean Cmax offospropofol of no less than 2000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 1500 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 1200 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 1000 ng/mL.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses results in a plasma Cmax or mean Cmax of fospropofolof no less than 800 ng/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 3200ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 2400ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 1600ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 800 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 600 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 400 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 300 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 200 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 100 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 50 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 3200 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 2400 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 1600 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 800 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 600 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 400 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 300 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 200 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 100 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol of no less than 50 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than8000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than7000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than6000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than5000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than4500 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than4000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than3000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than2000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than1000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 8000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 7000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 6000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 5000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 4500ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 4000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 3000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 2000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 1000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 300 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 200 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 150 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 100 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 50 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 30 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 20 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no less than 300 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no less than 200 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no less than 150 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no less than 100 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no less than 50 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no less than 30 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of propofol of no less than 20 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than7000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than6000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than5000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than4000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than3500 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than3000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than2000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than1000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 800ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 700ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 7000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 6000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 5000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 4000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 3500ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 3000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 2000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 1000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 800 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 700 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 800 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 700 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 600 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 500 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 400 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 300 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 200 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 100 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 800 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 700 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 600 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 500 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 400 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 300 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 200 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of propofol of no less than 100 nghr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC₄ hr or mean AUC_(4hr) of fospropofol of no greater than 12000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than8000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than7000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than6000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than5000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than4000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than3000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than2000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than1000 ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 12000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 8000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 7000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 6000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 5000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 4000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 3000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr), of fospropofol of no less than 2000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 1000ng hr/mL.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.2.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.29.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.2.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.29.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.2.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.23.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.2.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.23.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(20min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.68.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is lessthan 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.68.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(60min) ratio on a mean concentration vs. time curve that is atleast 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is lessthan 0.55.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(12min) ratio on a mean concentration vs. time curve that is lessthan 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.55.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(30min)/meanAUC_(120min) ratio on a mean concentration vs. time curve that is atleast 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is less than 1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is less than 0.9.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is less than 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is less than 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is less than 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is less than 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is less than 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is at least 1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is at least 0.9.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is at least 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is at least 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is at least 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is at least 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(2hr)ratio on a mean concentration vs. time curve that is at least 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.9.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.9.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(1hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.9.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is less than 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.9.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.7.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean AUC_(2hr)/mean AUC_(4hr)ratio on a mean concentration vs. time curve that is at least 0.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isless than 5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isless than 4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isless than 3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isless than 2.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isat least 5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isat least 4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isat least 3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₆₀ ratio that isat least 2.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isless than 80.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isless than 76.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isless than 70.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isless than 60.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isless than 50.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isat least 80.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isat least 76.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isat least 70.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isat least 60.

In some aspects of the methods of the disclosure, admimstering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₂₀/mean C₁₂₀ ratio that isat least 50.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isless than 3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isless than 2.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isless than 2.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isless than 2.0.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isless than 1.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isless than 1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isat least 3.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isat least 2.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isat least 2.4.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isat least 2.0.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isat least 1.5.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₆₀ ratio that isat least 1.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isless than 40.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isless than 36.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isless than 35.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isless than 30.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isless than 25.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isless than 20.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isless than 15.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isat least 40.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isat least 36.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isat least 35.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isat least 30.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isat least 25.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isat least 20.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C₃₀/mean C₁₂₀ ratio that isat least 15.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C_(1hr)/mean C_(4hr) ratiothat is less than 8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C_(1hr)/mean C_(4hr) ratiothat is at least 8.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C_(2hr)/mean C_(4hr) ratiothat is less than 6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C_(2hr)/mean C_(4hr) ratiothat is at least 6.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C_(1hr)/mean C_(2hr) ratiothat is less than 11.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma propofol or a plasma fospropofol mean C_(1hr)/mean C_(2hr) ratiothat is at least 11.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol nogreater than 40-80% of AUC_(0-∞), or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol nogreater than 40% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol nogreater than 50% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol nogreater than 60% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol nogreater than 70% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol nogreater than 80% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no lessthan 40-80% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no lessthan 40% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no lessthan 50% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no lessthan 60% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC₂ hr or mean AUC_(2hr) of propofol or of fospropofol no lessthan 70% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma AUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no lessthan 80% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-1600 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-1200 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-1000 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-800 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-600 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-400 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-200 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-1600 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-1200 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-1000 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-800 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-600 ng/mLfor at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-400 ng/mLfor at least 30 minutes. In some aspects of the methods of thedisclosure, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of fospropofol of 30-300 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-1700ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-1500ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-1300ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-1100ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-900ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-700ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-500ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1700ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1500ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1300ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1100ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-900ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-700ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-500ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1700ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1500ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1300ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1100ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-900ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-700ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-500ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-1600 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-1200 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-1000 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-800 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-600 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-400 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 100-200 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-1600 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-1200 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-1000 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-800 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-600 ng/mLfor at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol of 200-400 ng/mLfor at least 60 minutes. In some aspects of the methods of thedisclosure, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of fospropofol of 40-1700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-1500ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-1300ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-1100ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-900ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-700ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 40-500ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1700ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1500ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1300ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-1100ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-900ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-700ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 100-500ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1700ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1500ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1300ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-1100ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-900ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-700ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of fospropofol of 200-500ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-1600 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-1200 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-1000 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-800 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-600 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-400 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-200 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-1600 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-1200 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-1000 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-800 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-600 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-400 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-1600 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-1200 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-1000 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-800 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-600 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-400 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 100-200 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-1600 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-1200 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-1000 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-800 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-600 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of 200-400 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 30 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 40 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 50 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 100 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 150 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 180 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 200 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 300 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 400 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 500 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 600 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 800 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 30 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 40 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 50 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 75 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 100 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 150 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 200 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 300 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 400 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 500 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 600 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 800 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 30 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 40 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 50 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 75 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 100 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 150 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 200 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 300 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 400 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 500 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 600 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 700 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 800 ng/mL for at least 90 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 5 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 15 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 25 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 50 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 100 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 200 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 300 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 400 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 500 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 600 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 700 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol, or offospropofol, of at least 800 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol or of fospropofolat a time point 0.5-6 hr after Tmax or median Tmax that is 50-90% of thecorresponding plasma Cmax or mean Cmax of propofol or of fospropofol.

As used in these aspects, the term “the corresponding” means that theparameter corresponds to the analyte of interest. Thus, for example, ifone is considering the plasma concentration of propofol, then thecorresponding Tmax is that of propofol, and the corresponding Cmax isthat of propofol.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol or of fospropofol30 minutes after the corresponding Tmax or median Tmax that is 50-90% ofthe corresponding plasma Cmax or mean Cmax of propofol or offospropofol.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol or of fospropofol30 minutes after the corresponding Tmax or median Tmax that is about(i.e., the specified number±10%) 90% of the corresponding plasma Cmax ormean Cmax of propofol or of fospropofol.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol or of fospropofolat the time point 30 minutes after the corresponding Tmax or median Tmaxthat is about (i.e., the specified number±10%) 80% of the correspondingplasma Cmax or mean Cmax of propofol or of fospropofol.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol or of fospropofolat the time point 30 minutes after the corresponding Tmax or median Tmaxthat is about (i.e., the specified number±10%) 70% of the correspondingplasma Cmax or mean Cmax of propofol or of fospropofol.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol or of fospropofolat the time point 30 minutes after the corresponding Tmax or median Tmaxthat is about (i.e., the specified number±10%) 60% of the correspondingplasma Cmax or mean Cmax of propofol or of fospropofol.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aplasma concentration or mean concentration of propofol or of fospropofolat the time point 30 minutes after the corresponding Tmax or median Tmaxthat is about (i.e., the specified number±10%) 50% of the correspondingplasma Cmax or mean Cmax of propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1 hr afterthe corresponding Tmax or median Tmax that is 50-90% of thecorresponding plasma Cmax or mean Cmax of propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol at the time point 1 hr after the correspondingTmax or median Tmax that is about (i.e., the specified number±10%) 90%of the corresponding plasma Cmax or mean Cmax of propofol or offospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 80% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 70% of plasma Cmax or mean Cmax of propofol or offospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 60% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 50% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1.5 hr thecorresponding after Tmax or median Tmax that is 50-90% of thecorresponding plasma Cmax or mean Cmax of propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1.5 hrafter the corresponding Tmax or median Tmax that is about (i.e., thespecified number±10%) 90% of the corresponding plasma Cmax or mean Cmaxof propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1.5 hrafter the corresponding Tmax or median Tmax that is about (i.e., thespecified number±10%) 80% of the corresponding plasma Cmax or mean Cmaxof propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1.5 hrafter the corresponding Tmax or median Tmax that is about (i.e., thespecified number±10%) 70% of the corresponding plasma Cmax or mean Cmaxof propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1.5 hrafter the corresponding Tmax or median Tmax that is about (i.e., thespecified number±10%) 60% of the corresponding plasma Cmax or mean Cmaxof propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 1.5 hrafter the corresponding Tmax or median Tmax that is about (i.e., thespecified number±10%) 50% of the corresponding plasma Cmax or mean Cmaxof propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 2 hr afterthe corresponding Tmax or median Tmax that is 50-90% of thecorresponding plasma Cmax or mean Cmax of propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 2 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 90% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 2 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 80% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 2 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 70% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 2 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 60% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 2 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 50% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 3 hr afterthe corresponding Tmax or median Tmax that is 50-90% of thecorresponding plasma Cmax or mean Cmax of propofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 3 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 90% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 3 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 80% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 3 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 70% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 3 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 60% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a plasma concentration or meanconcentration of propofol or of fospropofol at the time point 3 hr afterthe corresponding Tmax or median Tmax that is about (i.e., the specifiednumber±10%) 50% of the corresponding plasma Cmax or mean Cmax ofpropofol or of fospropofol.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in apropofol or a fospropofol Tmax or median Tmax of 0.1 hr-2 hour.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in apropofol or a fospropofol Tmax or median Tmax of 20 min-4 hours.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in apropofol or a fospropofol Tmax or median Tmax of 30 min-4 hours.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in apropofol or a fospropofol Tmax or median Tmax of 60 min-4 hours.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aTmax or median Tmax for propofol of 0.6 hr-4 hours.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aTmax or median Tmax for propofol of 1 hr-2 hours.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aTmax or median Tmax for fospropofol of 0.1 hr-0.7 hours.

In some aspects of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in aTmax or median Tmax for fospropofol of 0.2 hr-0.5 hours. In someembodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 20 min.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 30 min.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 45 min.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 1 hr.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 1.5 hr.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 2.0 hr.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 2.5 hr.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 3.0 hr.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 3.5 hr.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a propofol or a fospropofol Tmax or medianTmax of about (i.e., the specified number±10%) 4.0 hr.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma Cmax for fospropofol has a coefficient ofvariation that is less than 55%, such as, for example, less than any oneof 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%.41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%,27%, 26%. 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%,13%, 12%, 11%, 10%. 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma Tmax for fospropofol has a coefficient ofvariation that is less than 39%, such as, for example, less than any oneof 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%. 26%,25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%,11%, 10%. 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma AUC_(1hr) for fospropofol has a coefficient ofvariation that is less than 58%, such as, for example, less than any oneof 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%. 48%, 47%, 46%, 45%.44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%,30%, 29%. 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%,16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma AUC_(2hr) for fospropofol has a coefficient ofvariation that is less than 57%, such as, for example, less than any oneof 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%.43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%,29%, 28%. 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%,15%, 14%, 13%, 12%. 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma AUC_(4hr) for fospropofol has a coefficient ofvariation that is less than 58%, such as, for example, less than any oneof 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%,44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%,30%, 29%. 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%,16%, 15%, 14%, 13%. 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma Cmax for propofol has a coefficient of variationthat is less than 68%, such as, for example, less than any one of 68%,67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%,53%. 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%,39%, 38%, 37%. 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%,25%, 24%, 23%, 22%, 21%. 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%,11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma Tmax for propofol has a coefficient of variationthat is less than 69%, such as, for example, less than any one of 69%,68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%,54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%,40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%,26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma AUC_(1hr) for propofol has a coefficient ofvariation that is less than 71%, such as, for example, less than any oneof 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%,57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%,43%, 42%, 41%, 40%. 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%,29%, 28%, 27%, 26%, 25%, 24%. 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%,15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma AUC_(2hr) for propofol has a coefficient ofvariation that is less than 65%, such as, for example, less than any oneof 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%,51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%,37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%,23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%,9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the mean plasma AUC_(4hr) for propofol has a coefficient ofvariation that is less than 56%, such as, for example, less than any oneof 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%,42%, 41%. 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%,28%, 27%, 26%, 25%. 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the plasma fospropofol mean AUC_(0-9 hrs) per mg of fospropofol(or a pharmaceutically acceptable salt of fospropofol) administered isat least 3.0 ng*h/mL, such as, for example, at least any one of 3.0ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2 ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6 ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0 ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4 ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8 ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2 ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6 ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0 ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4 ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8 ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2 ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6 ng*h/mL,/mg, 7.7 ng*h/mL/mg, 7.8ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0 ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4 ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8 ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the plasma fospropofol mean AUC_(0-∞) per mg of fospropofol (ora pharmaceutically acceptable salt of fospropofol) administered is atleast 3.0 ng*h/mL, such as, for example, at least any one of 3.0ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2 ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6 ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0 ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4 ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8 ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2 ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6 ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0 ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4 ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8 ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2 ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6 ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0 ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4 ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8 ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the plasma fospropofol mean C_(max) per mg of fospropofol (or apharmaceutically acceptable salt of fospropofol) administered is atleast 5.0 ng/mL/mg, such as, for example, at least any one of 5.0ng/mL/mg, 5.1 ng/mL/mg, 5.2 ng/mL/mg, 5.3 ng/mL/mg, 5.4 ng/mL/mg, 5.5ng/mL/mg, 5.6 ng/mL/mg, 5.7 ng/mL/mg, 5.8 ng/mL/mg, 5.9 ng/mL/mg, 6.0ng/mL/mg, 6.1 ng/mL/mg, 6.2 ng/mL/mg, 6.3 ng/mL/mg, 6.4 ng/mL/mg, 6.5ng/mL/mg, 6.6 ng/mL/mg, 6.7 ng/mL/mg, 6.8 ng/mL/mg, 6.9 ng/mL/mg, 7.0ng/mL/mg, 7.1 ng/mL/mg, 7.2 ng/mL/mg, 7.3 ng/mL/mg, 7.4 ng/mL/mg, 7.5ng/mL/mg, 7.6 ng/mL/mg, 7.7 ng/mL/mg, 7.8 ng/mL/mg, 7.9 ng/mL/mg, 8.0ng/mL/mg, 8.1 ng/mL/mg, 8.2 ng/mL/mg, 8.3 ng/mL/mg, 8.4 ng/mL/mg, 8.5ng/mL/mg, 8.6 ng/mL/mg, 8.7 ng/mL/mg, 8.8 ng/mL/mg, 8.9 ng/mL/mg, 9.0ng/mL/mg, 9.1 ng/mL/mg, 9.2 ng/mL/mg, 9.3 ng/mL/mg, 9.4 ng/mL/mg, 9.5ng/mL/mg, 9.6 ng/mL/mg, 9.7 ng/mL/mg, 9.8 ng/mL/mg, 9.9 ng/mL/mg, 10.0ng/mL/mg, 10.1 ng/mL/mg, 10.2 ng/mL/mg, 10.3 ng/mL/mg, 10.4 ng/mL/mg,10.5 ng/mL/mg, 10.6 ng/mL/mg, 10.7 ng/mL/mg, 10.8 ng/mL/mg, 10.9ng/mL/mg, 11.0 ng/mL/mg, 11.1 ng/mL/mg, 11.2 ng/mL/mg, 11.3 ng/mL/mg,11.4 ng/mL/mg, 11.5 ng/mL/mg, 11.6 ng/mL/mg, 11.7 ng/mL/mg, 11.8ng/mL/mg, 11.9 ng/mL/mg, 12.0 ng/mL/mg, 12.1 ng/mL/mg, 12.2 ng/mL/mg,12.3 ng/mL/mg, 12.4 ng/mL/mg, 12.5 ng/mL/mg, 12.6 ng/mL/mg, 12.7ng/mL/mg, 12.8 ng/mL/mg, 12.9 ng/mL/mg, 13.0 ng/mL/mg, 13.1 ng/mL/mg,13.2 ng/mL/mg, 13.3 ng/mL/mg, 13.4 ng/mL/mg, 13.5 ng/mL/mg, 13.6ng/mL/mg, 13.7 ng/mL/mg, 13.8 ng/mL/mg, 13.9 ng/mL/mg, 14.0 ng/mL/mg,14.1 ng/mL/mg, 14.2 ng/mL/mg, 14.3 ng/mL/mg, 14.4 ng/mL/mg, 14.5ng/mL/mg, 14.6 ng/mL/mg, 14.7 ng/mL/mg, 14.8 ng/mL/mg, 14.9 ng/mL/mg,15.0 ng/mL/mg, 15.1 ng/mL/mg, 15.2 ng/mL/mg, 15.3 ng/mL/mg, 15.4ng/mL/mg, 15.5 ng/mL/mg, 15.6 ng/mL/mg, 15.7 ng/mL/mg, 15.8 ng/mL/mg,15.9 ng/mL/mg, 16.0 ng/mL/mg, 16.1 ng/mL/mg, 16.2 ng/mL/mg, 16.3ng/mL/mg, 16.4 ng/mL/mg, 16.5 ng/mL/mg, 16.6 ng/mL/mg, 16.7 ng/mL/mg,16.8 ng/mL/mg, 16.9 ng/mL/mg, or 17.0 ng/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the plasma propofol mean AUC_(0-9 hrs) per mg of fospropofol (ora pharmaceutically acceptable salt of fospropofol) administered is atleast 0.5 ng*h/mL/mg, such as, for example, at least any one of 0.5ng*h/mL/mg, 0.55 ng*h/mL/mg, 0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8 ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0 ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2 ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4 ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6 ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the plasma propofol mean AUC_(0-∞) per mg of fospropofol (or apharmaceutically acceptable salt of fospropofol) administered is atleast 0.5 ng*h/mL/mg, such as, for example, at least any one of 0.5ng*h/mL/mg, 0.55 ng*h/mL/mg, 0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8 ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0 ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2 ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4 ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6 ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein the plasma propofol mean Cmax per mg of fospropofol (or apharmaceutically acceptable salt of fospropofol) administered is atleast 0.3 ng/mL/mg, such as, for example, at least any one of 0.3ng/mL/mg, 0.35 ng/mL/mg, 0.4 ng/mL/mg, 0.45 ng/mL/mg, 0.5 ng/mL/mg, 0.55ng/mL/mg, 0.6 ng/mL/mg, 0.65 ng/mL/mg, 0.7 ng/mL/mg, 0.75 ng/mL/mg, 0.8ng/mL/mg, 0.85 ng/mL/mg, or 0.9 ng/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hour of the administration at least 1%, at least 2%, atleast 3% at least 4%, at least 5%, at least 6%, at least 7%, at least8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%,at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, atleast 19%, or at least 20% of the patients are headache free withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 2 hours of the administration at least 5%, at least 10%,at least 15% at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, or at least 50%, of the patients are headachefree without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 4 hours of the at least 20%, at least 25%, at least 30%,at least 35% at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, or at least 75%, of the patientsare headache free without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 24 hours of the administration at least 50%, at least55%, at least 60%, at least 65%, at least 70%, or at least 75%, at least80%, at least 85%, at least 90%, or at least 95%, of the patients areheadache free without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 48 hours of the administration at least 50%, at least55%, at least 60%, at least 65%, at least 70%, or at least 75%, at least80%, at least 85%, at least 90%, or at least 95%, of the patients areheadache free without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hour of the administration at least 1%, at least 2%, atleast 3% at least 4%, at least 5%, at least 6%, at least 7%, at least8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%,at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, atleast 19%, or at least 20%, of the patients have experienced headachepain relief without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or at least 75%, ofthe patients have experienced headache pain relief without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 2 hours of the administration at least 50%, at least 55%,at least 60%, at least 65%, at least 70%, or at least 75%, at least 80%,at least 85%, at least 90%, or at least 95%, of the patients haveexperienced headache pain relief without being administered a rescuemedication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 4 hours of the administration at least 50%, at least 55%,at least 60%, at least 65%, at least 70%, or at least 75%, at least 80%,at least 85%, at least 90%, or at least 95%, of the patients haveexperienced headache pain relief without being administered a rescuemedication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 24 hours of the administration up to at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or at least 75%, atleast 80%, at least 85%, at least 90%, or at least 95% of the patientshave experienced headache pain relief without being administered arescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 48 hours of the administration at least 50%, at least55%, at least 60%, at least 65%, at least 70%, or at least 75%, at least80%, at least 85%, at least 90%, or at least 95%, of the patients haveexperienced headache pain relief without being administered a rescuemedication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hour of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or at least 75%, ofthe patients are free of their most bothersome symptom (MBS) withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 2 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, or atleast 80%, of the patients are free of their most bothersome symptom(MBS) without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 4 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, or atleast 80%, of the patients are free of their most bothersome symptom(MBS) without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 24 hours of the administration up to 80%, such as, forexample, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to55%, up to 50%, up to 45%, up to 40%, up to 35%, or up to 30%, of thepatients are free of their most bothersome symptom (MBS) without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 48 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, or at least 80%, of the patients are free of their most bothersomesymptom (MBS) without being administered a rescue medication.

In some embodiments of these methods, the MBS is nausea, photophobia, orphonophobia.

In some embodiments, the MBS is nausea.

In some embodiments, the MBS is photophobia.

In some embodiments, the MBS is phonophobia.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hour of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or at least 75%, ofthe patients are free of a bothersome symptom without being administereda rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 2 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, or atleast 80%, of the patients are free of a bothersome symptom withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 4 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, or atleast 80%, of the patients are free of a bothersome symptom withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 24 hours of the administration up to 80%, such as, forexample, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to55%, up to 50%, up to 45%, up to 40%, up to 35%, or up to 30%, of thepatients are free of a bothersome symptom without being administered arescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 48 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, or at least 80%, of the patients are free of a bothersome symptomwithout being administered a rescue medication.

In some embodiments of these methods, the bothersome symptom is nausea,photophobia, or phonophobia.

In some embodiments, the bothersome symptom is nausea.

In some embodiments, the bothersome symptom is photophobia.

In some embodiments, the bothersome symptom is phonophobia.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95%, of the patients whom hadnausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 2 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95%, of the patients whom hadnausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 4 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95%, of the patients whom hadnausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 24 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, or at least 95%, of the patients whomhad nausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 48 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, or at least 95%, of the patients whomhad nausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95%, of the patients whom hadphotophobia at administration are free of their photophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 2 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95%, of the patients whom hadphotophobia at administration are free of their photophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 4 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95% of the patients whom hadphotophobia at administration are free of their photophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 24 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, or at least 95%, of the patients whomhad photophobia at administration are free of their photophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 48 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, or at least 95%, of the patients whomhad photophobia at administration are free of their photophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 1 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95%, of the patients whom hadphonophobia at administration are free of their phonophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 2 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 850%, or at least 95%, of the patients whom hadphonophobia at administration are free of their phonophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 4 hours of the administration at least 20%, at least 25%,at least 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 95%, of the patients whom hadphonophobia at administration are free of their phonophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 24 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, or at least 95%, of the patients whomhad phonophobia at administration are free of their phonophobia withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,wherein within 48 hours of the administration at least 20%, at least25%, at least 30%, at least 35% at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, or at least 95%, of the patients whomhad phonophobia at administration are free of their phonophobia withoutbeing administered a rescue medication.

In some embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patientan effective amount of fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof, at 1 hour after the administrationthe subject is headache free.

In other embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patientan effective amount of fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof, at 1 hour after the administrationthe subject has experienced headache pain relief.

In some embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patientan effective amount of fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof, at 2 hour after the administrationthe subject is headache free.

In other embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patientan effective amount of fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof, at 2 hour after the administrationthe subject has experienced headache pain relief.

In some embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patientan effective amount of fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof, at 4 hour after the administrationthe subject is headache free.

In other embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patientan effective amount of fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof, at 4 hour after the administrationthe subject has experienced headache pain relief.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,sooner than 115 minutes after onset of migraine.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered sooner than 115 minutes after onset of migraine and theCmax of propofol is increased compared to administration after 115minutes.

In some aspects, the methods are directed to increasing the Cmax ofpropofol and treating migraine in a population of patients in needthereof with fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, wherein the fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof isadministered sooner than 115 minutes after onset of migraine.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isadministered as an acidified pharmaceutical dosage form and the Cmax ofpropofol does not decrease if the time to treatment from migraine onsetis delayed.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least 1000 ng*h/mL, such as, for example, at least 1000ng*h/mL, at least 1050 ng*h/mL, at least 1100 ng*h/mL, at least 1150ng*h/mL, at least 1200 ng*h/mL, at least 1250 ng*h/mL, at least 1300ng*h/mL, at least 1350 ng*h/mL, at least 1400 ng*h/mL, at least 1450ng*h/mL, at least 1500 ng*h/mL, at least 1550 ng*h/mL, at least 1600ng*h/mL, at least 1650 ng*h/mL, at least 1700 ng*h/mL, at least 1750ng*h/mL, at least 1800 ng*h/mL, at least 1850 ng*h/mL, at least 1900ng*h/mL, at least 1950 ng*h/mL, at least 2000 ng*h/mL, at least 2050ng*h/mL, at least 2100 ng*h/mL, at least 2150 ng*h/mL, at least 2200ng*h/mL, at least 2250 ng*h/mL, at least 2300 ng*h/mL, at least 2350ng*h/mL, at least 2400 ng*h/mL, at least 2450 ng*h/mL, at least 2500ng*h/mL, at least 2550 ng*h/mL, at least 2600 ng*h/mL, at least 2650ng*h/mL, at least 2700 ng*h/mL, at least 2750 ng*h/mL, at least 2800ng*h/mL, at least 2850 ng*h/mL, at least 2900 ng*h/mL, at least 2950ng*h/mL, at least 3000 ng*h/mL, at least 3050 ng*h/mL, at least 3100ng*h/mL, at least 3150 ng*h/mL, at least 3200 ng*h/mL, at least 3250ng*h/mL, at least 3300 ng*h/mL, at least 3350 ng*h/mL, at least 3400ng*h/mL, at least 3450 ng*h/mL, at least 3500 ng*h/mL, at least 3550ng*h/mL, at least 3600 ng*h/mL, at least 3650 ng*h/mL, at least 3700ng*h/mL, at least 3750 ng*h/mL, at least 3800 ng*h/mL, at least 3850ng*h/mL, at least 3900 ng*h/mL, at least 3950 ng*h/mL, at least 4000ng*h/mL, at least 4050 ng*h/mL, at least 4100 ng*h/mL, at least 4150ng*h/mL, at least 4200 ng*h/mL, at least 4250 ng*h/mL, at least 4300ng*h/mL, at least 4350 ng*h/mL, at least 4400 ng*h/mL, at least 4450ng*h/mL, at least 4500 ng*h/mL, at least 4550 ng*h/mL, at least 4600ng*h/mL, at least 4650 ng*h/mL, at least 4700 ng*h/mL, at least 4750ng*h/mL, at least 4800 ng*h/mL, at least 4850 ng*h/mL, at least 4900ng*h/mL, at least 4950 ng*h/mL, at least 5000 ng*h/mL, at least 5050ng*h/mL, at least 5100 ng*h/mL, at least 5150 ng*h/mL, at least 5200ng*h/mL, at least 5250 ng*h/mL, at least 5300 ng*h/mL, at least 5350ng*h/mL, at least 5400 ng*h/mL, at least 5450 ng*h/mL, at least 5500ng*h/mL, at least 5550 ng*h/mL, at least 5600 ng*h/mL, at least 5650ng*h/mL, at least 5700 ng*h/mL, at least 5750 ng*h/mL, at least 5800ng*h/mL, at least 5850 ng*h/mL, at least 5900 ng*h/mL, at least 5950ng*h/mL, at least 6000 ng*h/mL, at least 6050 ng*h/mL, at least 6100ng*h/mL, at least 6150 ng*h/mL, at least 6200 ng*h/mL, at least 6250ng*h/mL, at least 6300 ng*h/mL, at least 6350 ng*h/mL, at least 6400ng*h/mL, at least 6450 ng*h/mL, at least 6500 ng*h/mL, at least 6550ng*h/mL, at least 6600 ng*h/mL, at least 6650 ng*h/mL, at least 6700ng*h/mL, at least 6750 ng*h/mL, at least 6800 ng*h/mL, at least 6850ng*h/mL, at least 6900 ng*h/mL, at least 6950 ng*h/mL, at least 7000ng*h/mL, at least 7050 ng*h/mL, at least 7100 ng*h/mL, at least 7150ng*h/mL, at least 7200 ng*h/mL, at least 7250 ng*h/mL, at least 7300ng*h/mL, at least 7350 ng*h/mL, at least 7400 ng*h/mL, at least 7450ng*h/mL, at least 7500 ng*h/mL, at least 7550 ng*h/mL, at least 7600ng*h/mL, at least 7650 ng*h/mL, at least 7700 ng*h/mL, at least 7750ng*h/mL, at least 7800 ng*h/mL, at least 7850 ng*h/mL, at least 7900ng*h/mL, at least 7950 ng*h/mL, at least 8000 ng*h/mL, at least 8050ng*h/mL, at least 8100 ng*h/mL, at least 8150 ng*h/mL, at least 8200ng*h/mL, at least 8250 ng*h/mL, at least 8300 ng*h/mL, at least 8350ng*h/mL, at least 8400 ng*h/mL, at least 8450 ng*h/mL, at least 8500ng*h/mL, at least 8550 ng*h/mL, at least 8600 ng*h/mL, at least 8650ng*h/mL, at least 8700 ng*h/mL, at least 8750 ng*h/mL, at least 8800ng*h/mL, at least 8850 ng*h/mL, at least 8900 ng*h/mL, at least 8950ng*h/mL, at least 9000 ng*h/mL, at least 9050 ng*h/mL, at least 9100ng*h/mL, at least 9150 ng*h/mL, at least 9200 ng*h/mL, at least 9250ng*h/mL, at least 9300 ng*h/mL, at least 9350 ng*h/mL, at least 9400ng*h/mL, at least 9450 ng*h/mL, at least 9500 ng*h/mL, at least 9550ng*h/mL, at least 9600 ng*h/mL, at least 9650 ng*h/mL, at least 9700ng*h/mL, at least 9750 ng*h/mL, at least 9800 ng*h/mL, at least 9850ng*h/mL, at least 9900 ng*h/mL, at least 9950 ng*h/mL, or at least 10000ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol AUC_(1hr) or the patient population has a meanAUC_(1hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least 6000 ng*h/mL and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol AUC_(1hr) or the patient population has a meanAUC_(1hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least 2000 ng*h/mL and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol AUC_(1hr) or the patient population has a meanAUC_(1hr) as set forth herein and the patient is no longer experiencingits most bothersome symptom. In some embodiments, the MBS is nausea,photophobia, or phonophobia. In some embodiments, the MBS is nausea,photophobia, or phonophobia. In some embodiments, the MBS is nausea. Insome embodiments, the MBS is photophobia. In some embodiments, the MBSis phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least 3000 ng*h/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas a plasma fospropofol concentration (C_(1hr)) or the patientpopulation has a mean C_(1hr) of at least 500 ng/mL, such as, forexample, at least 500 ng/mL, at least 550 ng/mL, at least 600 ng/mL, atleast 650 ng/mL, at least 700 ng/mL, at least 750 ng/mL, at least 800ng/mL, at least 850 ng/mL, at least 900 ng/mL, at least 950 ng/mL, 1000ng/mL, such as, for example, at least 1000 ng/mL, at least 1050 ng/mL,at least 1100 ng/mL, at least 1150 ng/mL, at least 1200 ng/mL, at least1250 ng/mL, at least 1300 ng/mL, at least 1350 ng/mL, at least 1400ng/mL, at least 1450 ng/mL, at least 1500 ng/mL, at least 1550 ng/mL, atleast 1600 ng/mL, at least 1650 ng/mL, at least 1700 ng/mL, at least1750 ng/mL, at least 1800 ng/mL, at least 1850 ng/mL, at least 1900ng/mL, at least 1950 ng/mL, at least 2000 ng/mL, at least 2050 ng/mL, atleast 2100 ng/mL, at least 2150 ng/mL, at least 2200 ng/mL, at least2250 ng/mL, at least 2300 ng/mL, at least 2350 ng/mL, at least 2400ng/mL, at least 2450 ng/mL, at least 2500 ng/mL, at least 2550 ng/mL, atleast 2600 ng/mL, at least 2650 ng/mL, at least 2700 ng/mL, at least2750 ng/mL, at least 2800 ng/mL, at least 2850 ng/mL, at least 2900ng/mL, at least 2950 ng/mL, at least 3000 ng/mL, at least 3050 ng/mL, atleast 3100 ng/mL, at least 3150 ng/mL, at least 3200 ng/mL, at least3250 ng/mL, at least 3300 ng/mL, at least 3350 ng/mL, at least 3400ng/mL, at least 3450 ng/mL, at least 3500 ng/mL, at least 3550 ng/mL, atleast 3600 ng/mL, at least 3650 ng/mL, at least 3700 ng/mL, at least3750 ng/mL, at least 3800 ng/mL, at least 3850 ng/mL, at least 3900ng/mL, at least 3950 ng/mL, at least 4000 ng/mL, at least 4050 ng/mL, atleast 4100 ng/mL, at least 4150 ng/mL, at least 4200 ng/mL, at least4250 ng/mL, at least 4300 ng/mL, at least 4350 ng/mL, at least 4400ng/mL, at least 4450 ng/mL, at least 4500 ng/mL, at least 4550 ng/mL, atleast 4600 ng/mL, at least 4650 ng/mL, at least 4700 ng/mL, at least4750 ng/mL, at least 4800 ng/mL, at least 4850 ng/mL, at least 4900ng/mL, at least 4950 ng/mL, or at least 5000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas a plasma fospropofol concentration (C_(1hr)) or the patientpopulation has a mean C_(1hr) as set forth herein and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) of at least 2000 ng/mL and the patient is headachefree.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) of at least 1000 ng/mL and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) as set forth herein and the patient is no longerexperiencing its most bothersome symptom. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma fospropofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) of at least 1000 ng/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least 1000 ng*h/mL, such as, for example, at least1000 ng*h/mL, at least 1050 ng*h/mL, at least 1100 ng*h/mL, at least1150 ng*h/mL, at least 1200 ng*h/mL, at least 1250 ng*h/mL, at least1300 ng*h/mL, at least 1350 ng*h/mL, at least 1400 ng*h/mL, at least1450 ng*h/mL, at least 1500 ng*h/mL, at least 1550 ng*h/mL, at least1600 ng*h/mL, at least 1650 ng*h/mL, at least 1700 ng*h/mL, at least1750 ng*h/mL, at least 1800 ng*h/mL, at least 1850 ng*h/mL, at least1900 ng*h/mL, at least 1950 ng*h/mL, at least 2000 ng*h/mL, at least2050 ng*h/mL, at least 2100 ng*h/mL, at least 2150 ng*h/mL, at least2200 ng*h/mL, at least 2250 ng*h/mL, at least 2300 ng*h/mL, at least2350 ng*h/mL, at least 2400 ng*h/mL, at least 2450 ng*h/mL, at least2500 ng*h/mL, at least 2550 ng*h/mL, at least 2600 ng*h/mL, at least2650 ng*h/mL, at least 2700 ng*h/mL, at least 2750 ng*h/mL, at least2800 ng*h/mL, at least 2850 ng*h/mL, at least 2900 ng*h/mL, at least2950 ng*h/mL, at least 3000 ng*h/mL, at least 3050 ng*h/mL, at least3100 ng*h/mL, at least 3150 ng*h/mL, at least 3200 ng*h/mL, at least3250 ng*h/mL, at least 3300 ng*h/mL, at least 3350 ng*h/mL, at least3400 ng*h/mL, at least 3450 ng*h/mL, at least 3500 ng*h/mL, at least3550 ng*h/mL, at least 3600 ng*h/mL, at least 3650 ng*h/mL, at least3700 ng*h/mL, at least 3750 ng*h/mL, at least 3800 ng*h/mL, at least3850 ng*h/mL, at least 3900 ng*h/mL, at least 3950 ng*h/mL, at least4000 ng*h/mL, at least 4050 ng*h/mL, at least 4100 ng*h/mL, at least4150 ng*h/mL, at least 4200 ng*h/mL, at least 4250 ng*h/mL, at least4300 ng*h/mL, at least 4350 ng*h/mL, at least 4400 ng*h/mL, at least4450 ng*h/mL, at least 4500 ng*h/mL, at least 4550 ng*h/mL, at least4600 ng*h/mL, at least 4650 ng*h/mL, at least 4700 ng*h/mL, at least4750 ng*h/mL, at least 4800 ng*h/mL, at least 4850 ng*h/mL, at least4900 ng*h/mL, at least 4950 ng*h/mL, at least 5000 ng*h/mL, at least5050 ng*h/mL, at least 5100 ng*h/mL, at least 5150 ng*h/mL, at least5200 ng*h/mL, at least 5250 ng*h/mL, at least 5300 ng*h/mL, at least5350 ng*h/mL, at least 5400 ng*h/mL, at least 5450 ng*h/mL, at least5500 ng*h/mL, at least 5550 ng*h/mL, at least 5600 ng*h/mL, at least5650 ng*h/mL, at least 5700 ng*h/mL, at least 5750 ng*h/mL, at least5800 ng*h/mL, at least 5850 ng*h/mL, at least 5900 ng*h/mL, at least5950 ng*h/mL, at least 6000 ng*h/mL, at least 6050 ng*h/mL, at least6100 ng*h/mL, at least 6150 ng*h/mL, at least 6200 ng*h/mL, at least6250 ng*h/mL, at least 6300 ng*h/mL, at least 6350 ng*h/mL, at least6400 ng*h/mL, at least 6450 ng*h/mL, at least 6500 ng*h/mL, at least6550 ng*h/mL, at least 6600 ng*h/mL, at least 6650 ng*h/mL, at least6700 ng*h/mL, at least 6750 ng*h/mL, at least 6800 ng*h/mL, at least6850 ng*h/mL, at least 6900 ng*h/mL, at least 6950 ng*h/mL, at least7000 ng*h/mL, at least 7050 ng*h/mL, at least 7100 ng*h/mL, at least7150 ng*h/mL, at least 7200 ng*h/mL, at least 7250 ng*h/mL, at least7300 ng*h/mL, at least 7350 ng*h/mL, at least 7400 ng*h/mL, at least7450 ng*h/mL, at least 7500 ng*h/mL, at least 7550 ng*h/mL, at least7600 ng*h/mL, at least 7650 ng*h/mL, at least 7700 ng*h/mL, at least7750 ng*h/mL, at least 7800 ng*h/mL, at least 7850 ng*h/mL, at least7900 ng*h/mL, at least 7950 ng*h/mL, at least 8000 ng*h/mL, at least8050 ng*h/mL, at least 8100 ng*h/mL, at least 8150 ng*h/mL, at least8200 ng*h/mL, at least 8250 ng*h/mL, at least 8300 ng*h/mL, at least8350 ng*h/mL, at least 8400 ng*h/mL, at least 8450 ng*h/mL, at least8500 ng*h/mL, at least 8550 ng*h/mL, at least 8600 ng*h/mL, at least8650 ng*h/mL, at least 8700 ng*h/mL, at least 8750 ng*h/mL, at least8800 ng*h/mL, at least 8850 ng*h/mL, at least 8900 ng*h/mL, at least8950 ng*h/mL, at least 9000 ng*h/mL, at least 9050 ng*h/mL, at least9100 ng*h/mL, at least 9150 ng*h/mL, at least 9200 ng*h/mL, at least9250 ng*h/mL, at least 9300 ng*h/mL, at least 9350 ng*h/mL, at least9400 ng*h/mL, at least 9450 ng*h/mL, at least 9500 ng*h/mL, at least9550 ng*h/mL, at least 9600 ng*h/mL, at least 9650 ng*h/mL, at least9700 ng*h/mL, at least 9750 ng*h/mL, at least 9800 ng*h/mL, at least9850 ng*h/mL, at least 9900 ng*h/mL, at least 9950 ng*h/mL, or at least10000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol AUC_(2hr) or the patient population has amean AUC_(2hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least 3000 ng*h/mL and the patient is headachefree.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol AUC_(2hr) or the patient population has amean AUC_(2hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least 1000 ng*h/mL and the patient has experienceda reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol AUC_(2hr) or the patient population has amean AUC_(2hr) as set forth herein and the patient is no longerexperiencing its most bothersome symptom. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least 1000 ng*h/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hour after the administration the patienthas plasma fospropofol concentration (C_(2hr)) or the patient populationhas a mean C_(2hr) of at least 25 ng/mL, such as, for example, at least25 ng/mL, at least 50 ng/mL, at least 75 ng/mL, at least 100 ng/mL, atleast 125 ng/mL, at least 150 ng/mL, at least 175 ng/mL, at least 200ng/mL, at least 225 ng/mL, at least 250 ng/mL, 275 ng/mL, at least 300ng/mL, at least 325 ng/mL, at least 350 ng/mL, at least 400 ng/mL, atleast 425 ng/mL, at least 450 ng/mL, at least 475 ng/mL, at least 500ng/mL, at least 525 ng/mL, at least 550 ng/mL, at least 575 ng/mL, atleast 600 ng/mL, at least 625 ng/mL, at least 650 ng/mL, at least 675ng/mL, at least 700 ng/mL, at least 725 ng/mL, at least 750 ng/mL, atleast 775 ng/mL, at least 800 ng/mL, at least 825 ng/mL, at least 850ng/mL, at least 875 ng/mL, at least 900 ng/mL, at least 925 ng/mL, atleast 950 ng/mL, at least 975 ng/mL, at least 1000 ng/mL, at least 1100ng/mL, at least 1125 ng/mL, at least 1150 ng/mL, at least 1175 ng/mL, atleast 1200 ng/mL, at least 1225 ng/mL, at least 1250 ng/mL, 1275 ng/mL,at least 1300 ng/mL, at least 1325 ng/mL, at least 1350 ng/mL, at least1400 ng/mL, at least 1425 ng/mL, at least 1450 ng/mL, at least 1475ng/mL, at least 1500 ng/mL, at least 1525 ng/mL, at least 1550 ng/mL, atleast 1575 ng/mL, at least 1600 ng/mL, at least 1625 ng/mL, at least1650 ng/mL, at least 1675 ng/mL, at least 1700 ng/mL, at least 1725ng/mL, at least 1750 ng/mL, at least 1775 ng/mL, at least 1800 ng/mL, atleast 1825 ng/mL, at least 1850 ng/mL, at least 1875 ng/mL, at least1900 ng/mL, at least 1925 ng/mL, at least 1950 ng/mL, at least 1975ng/mL, or at least 2000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has a plasma fospropofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) as set forth herein and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hour after the administration the patienthas plasma fospropofol concentration (C_(2hr)) or the patient populationhas a mean C_(2hr) of at least 100 ng/mL and the patient is headachefree.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) as set forth herein and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) of at least 40 ng/mL and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) as set forth herein and the patient is nolonger experiencing its most bothersome symptom. In some embodiments,the MBS is nausea, photophobia, or phonophobia. In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma fospropofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) of at least 50 ng/mL and the patient is nolonger experiencing its most bothersome symptom (MBS). In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom, and the plasma Cmax or the patientpopulation mean Cmax of propofol is at least any one of 200 ng/mL, 250ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL,600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800ng/mL, 1850 ng/mL, 1900 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3050ng/mL, 3100 ng/mL, 3150 ng/mL, 3200 ng/mL, 3250 ng/mL, 3300 ng/mL, 3350ng/mL, 3400 ng/mL, 3450 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950ng/mL, or 4000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the plasma Cmax or the patientpopulation mean Cmax of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) is at least any one of 800 ng/mL, 850 ng/mL, 900ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800ng/mL, 1850 ng/mL, 1900 ng/mL, 1950 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL, 9950 ng/mL, 10000 ng/mL,10050 ng/mL, 10100 ng/mL, 10150 ng/mL, 10200 ng/mL, 10250 ng/mL, 10300ng/mL, 10350 ng/mL, 10400 ng/mL, 10450 ng/mL, 10500 ng/mL, 10550 ng/mL,10600 ng/mL, 10650 ng/mL, 10700 ng/mL, 10750 ng/mL, 1000 ng/mL, 101050ng/mL, 10900 ng/mL, 10950 ng/mL, 11000 ng/mL, 11050 ng/mL, 11100 ng/mL,11150 ng/mL, 11200 ng/mL, 11250 ng/mL, 11300 ng/mL, 11350 ng/mL, 11400ng/mL, 11450 ng/mL, 11500 ng/mL, 11550 ng/mL, 11600 ng/mL, 11650 ng/mL,11700 ng/mL, 11750 ng/mL, 1100 ng/mL, 111150 ng/mL, 11900 ng/mL, 11950ng/mL, 12000 ng/mL, 12050 ng/mL, 12100 ng/mL, 12150 ng/mL, 12200 ng/mL,12250 ng/mL, 12300 ng/mL, 12350 ng/mL, 12400 ng/mL, 12450 ng/mL, 12500ng/mL, 12550 ng/mL, 12600 ng/mL, 12650 ng/mL, 12700 ng/mL, 12750 ng/mL,1200 ng/mL, 121250 ng/mL, 12900 ng/mL, 12950 ng/mL, 13000 ng/mL, 13050ng/mL, 13100 ng/mL, 13150 ng/mL, 13200 ng/mL, 13250 ng/mL, 13300 ng/mL,13350 ng/mL, 13400 ng/mL, 13450 ng/mL, 13500 ng/mL, 13550 ng/mL, 13600ng/mL, 13650 ng/mL, 13700 ng/mL, 13750 ng/mL, 1300 ng/mL, 131350 ng/mL,13900 ng/mL, 13950 ng/mL, 14000 ng/mL, 14050 ng/mL, 14100 ng/mL, 14150ng/mL, 14200 ng/mL, 14250 ng/mL, 14300 ng/mL, 14350 ng/mL, 14400 ng/mL,14450 ng/mL, 14500 ng/mL, 14550 ng/mL, 14600 ng/mL, 14650 ng/mL, 14700ng/mL, 14750 ng/mL, 1400 ng/mL, 141450 ng/mL, 14900 ng/mL, 14950 ng/mL,15000 ng/mL, 15050 ng/mL, 15100 ng/mL, 15150 ng/mL, 15200 ng/mL, 15250ng/mL, 15300 ng/mL, 15350 ng/mL, 15400 ng/mL, 15450 ng/mL, 15500 ng/mL,15550 ng/mL, 15600 ng/mL, 15650 ng/mL, 15700 ng/mL, 15750 ng/mL, 1500ng/mL, 151550 ng/mL, 15900 ng/mL, 15950 ng/mL, 16000 ng/mL, 16050 ng/mL,16100 ng/mL, 16150 ng/mL, 16200 ng/mL, 16250 ng/mL, 16300 ng/mL, 16350ng/mL, 16400 ng/mL, 16450 ng/mL, 16500 ng/mL, 16550 ng/mL, 16600 ng/mL,16650 ng/mL, 16700 ng/mL, 16750 ng/mL, 1600 ng/mL, 161650 ng/mL, 16900ng/mL, 16950 ng/mL, 17000 ng/mL, 17050 ng/mL, 17100 ng/mL, 17150 ng/mL,17200 ng/mL, 17250 ng/mL, 17300 ng/mL, 17350 ng/mL, 17400 ng/mL, 17450ng/mL, 17500 ng/mL, 17550 ng/mL, 17600 ng/mL, 17650 ng/mL, 17700 ng/mL,17750 ng/mL, 1700 ng/mL, 171750 ng/mL, 17900 ng/mL, 17950 ng/mL, or18000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the propofol plasma AUC_(0-∞) permg of fospropofol (or a pharmaceutically acceptable salt of fospropofol)administered or the propofol patient population mean AUC_(0-∞) per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is, at least any one of 0.5 ng*h/mL/mg, 0.55 ng*h/mL/mg,0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7 ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9 ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10 ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3 ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5 ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the fospropofol plasma AUC_(0-∞)per mg of fospropofol (or a pharmaceutically acceptable salt offospropofol) administered or the fospropofol patient population meanAUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptable saltof fospropofol) administered is at least 3.0 ng*h/mL, such as, forexample, at least any one of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8 ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2 ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6 ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0 ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4 ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8 ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2 ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6 ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0 ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4 ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8 ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2 ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6 ng*h/mL/mg, 8.7 ng*h/mL/mg 8.8ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patientis headache free, has experienced a reduction in headache pain, is nolonger experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom, and the plasma Cmax or the patientpopulation mean Cmax of propofol is at least any one of 200 ng/mL, 250ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL,600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800ng/mL, 1850 ng/mL, 1900 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3050ng/mL, 3100 ng/mL, 3150 ng/mL, 3200 ng/mL, 3250 ng/mL, 3300 ng/mL, 3350ng/mL, 3400 ng/mL, 3450 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950ng/mL, or 4000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patientis headache free, has experienced a reduction in headache pain, is nolonger experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the plasma Cmax or the patientpopulation mean Cmax of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) is at least any one of 800 ng/mL, 850 ng/mL, 900ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800ng/mL, 1850 ng/mL, 1900 ng/mL, 1950 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL, 9950 ng/mL, 10000 ng/mL,10050 ng/mL, 10100 ng/mL, 10150 ng/mL, 10200 ng/mL, 10250 ng/mL, 10300ng/mL, 10350 ng/mL, 10400 ng/mL, 10450 ng/mL, 10500 ng/mL, 10550 ng/mL,10600 ng/mL, 10650 ng/mL, 10700 ng/mL, 10750 ng/mL, 1000 ng/mL, 101050ng/mL, 10900 ng/mL, 10950 ng/mL, 11000 ng/mL, 11050 ng/mL, 11100 ng/mL,11150 ng/mL, 11200 ng/mL, 11250 ng/mL, 11300 ng/mL, 11350 ng/mL, 11400ng/mL, 11450 ng/mL, 11500 ng/mL, 11550 ng/mL, 11600 ng/mL, 11650 ng/mL,11700 ng/mL, 11750 ng/mL, 1100 ng/mL, 111150 ng/mL, 11900 ng/mL, 11950ng/mL, 12000 ng/mL, 12050 ng/mL, 12100 ng/mL, 12150 ng/mL, 12200 ng/mL,12250 ng/mL, 12300 ng/mL, 12350 ng/mL, 12400 ng/mL, 12450 ng/mL, 12500ng/mL, 12550 ng/mL, 12600 ng/mL, 12650 ng/mL, 12700 ng/mL, 12750 ng/mL,1200 ng/mL, 121250 ng/mL, 12900 ng/mL, 12950 ng/mL, 13000 ng/mL, 13050ng/mL, 13100 ng/mL, 13150 ng/mL, 13200 ng/mL, 13250 ng/mL, 13300 ng/mL,13350 ng/mL, 13400 ng/mL, 13450 ng/mL, 13500 ng/mL, 13550 ng/mL, 13600ng/mL, 13650 ng/mL, 13700 ng/mL, 13750 ng/mL, 1300 ng/mL, 131350 ng/mL,13900 ng/mL, 13950 ng/mL, 14000 ng/mL, 14050 ng/mL, 14100 ng/mL, 14150ng/mL, 14200 ng/mL, 14250 ng/mL, 14300 ng/mL, 14350 ng/mL, 14400 ng/mL,14450 ng/mL, 14500 ng/mL, 14550 ng/mL, 14600 ng/mL, 14650 ng/mL, 14700ng/mL, 14750 ng/mL, 1400 ng/mL, 141450 ng/mL, 14900 ng/mL, 14950 ng/mL,15000 ng/mL, 15050 ng/mL, 15100 ng/mL, 15150 ng/mL, 15200 ng/mL, 15250ng/mL, 15300 ng/mL, 15350 ng/mL, 15400 ng/mL, 15450 ng/mL, 15500 ng/mL,15550 ng/mL, 15600 ng/mL, 15650 ng/mL, 15700 ng/mL, 15750 ng/mL, 1500ng/mL, 151550 ng/mL, 15900 ng/mL, 15950 ng/mL, 16000 ng/mL, 16050 ng/mL,16100 ng/mL, 16150 ng/mL, 16200 ng/mL, 16250 ng/mL, 16300 ng/mL, 16350ng/mL, 16400 ng/mL, 16450 ng/mL, 16500 ng/mL, 16550 ng/mL, 16600 ng/mL,16650 ng/mL, 16700 ng/mL, 16750 ng/mL, 1600 ng/mL, 161650 ng/mL, 16900ng/mL, 16950 ng/mL, 17000 ng/mL, 17050 ng/mL, 17100 ng/mL, 17150 ng/mL,17200 ng/mL, 17250 ng/mL, 17300 ng/mL, 17350 ng/mL, 17400 ng/mL, 17450ng/mL, 17500 ng/mL, 17550 ng/mL, 17600 ng/mL, 17650 ng/mL, 17700 ng/mL,17750 ng/mL, 1700 ng/mL, 171750 ng/mL, 17900 ng/mL, 17950 ng/mL, or18000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patientis headache free, has experienced a reduction in headache pain, is nolonger experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the propofol plasma AUC_(0-∞) permg of fospropofol (or a pharmaceutically acceptable salt of fospropofol)administered or the propofol patient population mean AUC_(0-∞) per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is, at least any one of 0.5 ng*h/mL/mg, 0.55 ng*h/mL/mg,0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7 ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9 ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10 ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3 ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5 ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patientis headache free, has experienced a reduction in headache pain, is nolonger experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the fospropofol plasma AUC_(0-∞)per mg of fospropofol (or a pharmaceutically acceptable salt offospropofol) administered or the fospropofol patient population meanAUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptable saltof fospropofol) administered is at least 3.0 ng*h/mL, such as, forexample, at least any one of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8 ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2 ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6 ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0 ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4 ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8 ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2 ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6 ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8ng*h/mL/mg. 6.9 ng*h/mL/mg, 7.0 ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2ng*h/mL/mg, 7.3 ng*h/mL/mg. 7.4 ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8 ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2 ng*h/mL/mg, 8.3 ng*h/mL/mg. 8.4ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6 ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8ng*h/mL/mg. 8.9 ng*h/mL/mg, or 9.0 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom, and the plasma Cmax or the patientpopulation mean Cmax of propofol is at least any one of 200 ng/mL, 250ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL,600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800ng/mL, 1850 ng/mL, 1900 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3050ng/mL, 3100 ng/mL, 3150 ng/mL, 3200 ng/mL, 3250 ng/mL, 3300 ng/mL, 3350ng/mL, 3400 ng/mL, 3450 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950ng/mL, or 4000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the plasma Cmax or the patientpopulation mean Cmax of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) is at least any one of 800 ng/mL, 850 ng/mL, 900ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800ng/mL, 1850 ng/mL, 1900 ng/mL, 1950 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL, 9950 ng/mL, 10000 ng/mL,10050 ng/mL, 10100 ng/mL, 10150 ng/mL, 10200 ng/mL, 10250 ng/mL, 10300ng/mL, 10350 ng/mL, 10400 ng/mL, 10450 ng/mL, 10500 ng/mL, 10550 ng/mL,10600 ng/mL, 10650 ng/mL, 10700 ng/mL, 10750 ng/mL, 1000 ng/mL, 101050ng/mL, 10900 ng/mL, 10950 ng/mL, 11000 ng/mL, 11050 ng/mL, 11100 ng/mL,11150 ng/mL, 11200 ng/mL, 11250 ng/mL, 11300 ng/mL, 11350 ng/mL, 11400ng/mL, 11450 ng/mL, 11500 ng/mL, 11550 ng/mL, 11600 ng/mL, 11650 ng/mL,11700 ng/mL, 11750 ng/mL, 1100 ng/mL, 111150 ng/mL, 11900 ng/mL, 11950ng/mL, 12000 ng/mL, 12050 ng/mL, 12100 ng/mL, 12150 ng/mL, 12200 ng/mL,12250 ng/mL, 12300 ng/mL, 12350 ng/mL, 12400 ng/mL, 12450 ng/mL, 12500ng/mL, 12550 ng/mL, 12600 ng/mL, 12650 ng/mL, 12700 ng/mL, 12750 ng/mL,1200 ng/mL, 121250 ng/mL, 12900 ng/mL, 12950 ng/mL, 13000 ng/mL, 13050ng/mL, 13100 ng/mL, 13150 ng/mL, 13200 ng/mL, 13250 ng/mL, 13300 ng/mL,13350 ng/mL, 13400 ng/mL, 13450 ng/mL, 13500 ng/mL, 13550 ng/mL, 13600ng/mL, 13650 ng/mL, 13700 ng/mL, 13750 ng/mL, 1300 ng/mL, 131350 ng/mL,13900 ng/mL, 13950 ng/mL, 14000 ng/mL, 14050 ng/mL, 14100 ng/mL, 14150ng/mL, 14200 ng/mL, 14250 ng/mL, 14300 ng/mL, 14350 ng/mL, 14400 ng/mL,14450 ng/mL, 14500 ng/mL, 14550 ng/mL, 14600 ng/mL, 14650 ng/mL, 14700ng/mL, 14750 ng/mL, 1400 ng/mL, 141450 ng/mL, 14900 ng/mL, 14950 ng/mL,15000 ng/mL, 15050 ng/mL, 15100 ng/mL, 15150 ng/mL, 15200 ng/mL, 15250ng/mL, 15300 ng/mL, 15350 ng/mL, 15400 ng/mL, 15450 ng/mL, 15500 ng/mL,15550 ng/mL, 15600 ng/mL, 15650 ng/mL, 15700 ng/mL, 15750 ng/mL, 1500ng/mL, 151550 ng/mL, 15900 ng/mL, 15950 ng/mL, 16000 ng/mL, 16050 ng/mL,16100 ng/mL, 16150 ng/mL, 16200 ng/mL, 16250 ng/mL, 16300 ng/mL, 16350ng/mL, 16400 ng/mL, 16450 ng/mL, 16500 ng/mL, 16550 ng/mL, 16600 ng/mL,16650 ng/mL, 16700 ng/mL, 16750 ng/mL, 1600 ng/mL, 161650 ng/mL, 16900ng/mL, 16950 ng/mL, 17000 ng/mL, 17050 ng/mL, 17100 ng/mL, 17150 ng/mL,17200 ng/mL, 17250 ng/mL, 17300 ng/mL, 17350 ng/mL, 17400 ng/mL, 17450ng/mL, 17500 ng/mL, 17550 ng/mL, 17600 ng/mL, 17650 ng/mL, 17700 ng/mL,17750 ng/mL, 1700 ng/mL, 171750 ng/mL, 17900 ng/mL, 17950 ng/mL, or18000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the propofol plasma AUC_(0-∞) permg of fospropofol (or a pharmaceutically acceptable salt of fospropofol)administered or the propofol patient population mean AUC_(0-∞) per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is, at least any one of 0.5 ng*h/mL/mg, 0.55 ng*h/mL/mg,0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7 ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9 ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10 ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3 ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5 ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient is headache free, has experienced a reduction in headache pain,is no longer experiencing a most bothersome symptom, or is no longerexperiencing a bothersome symptom and the fospropofol plasma AUC_(0-∞)per mg of fospropofol (or a pharmaceutically acceptable salt offospropofol) administered or the fospropofol patient population meanAUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptable saltof fospropofol) administered is at least 3.0 ng*h/mL, such as, forexample, at least any one of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8 ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2 ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6 ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0 ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4 ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8 ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2 ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6 ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0 ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4 ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8 ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2 ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6 ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least 1000 ng*h/mL, such as, for example, at least1000 ng*h/mL, at least 1050 ng*h/mL, at least 1100 ng*h/mL, at least1150 ng*h/mL, at least 1200 ng*h/mL, at least 1250 ng*h/mL, at least1300 ng*h/mL, at least 1350 ng*h/mL, at least 1400 ng*h/mL, at least1450 ng*h/mL, at least 1500 ng*h/mL, at least 1550 ng*h/mL, at least1600 ng*h/mL, at least 1650 ng*h/mL, at least 1700 ng*h/mL, at least1750 ng*h/mL, at least 1800 ng*h/mL, at least 1850 ng*h/mL, at least1900 ng*h/mL, at least 1950 ng*h/mL, at least 2000 ng*h/mL, at least2050 ng*h/mL, at least 2100 ng*h/mL, at least 2150 ng*h/mL, at least2200 ng*h/mL, at least 2250 ng*h/mL, at least 2300 ng*h/mL, at least2350 ng*h/mL, at least 2400 ng*h/mL, at least 2450 ng*h/mL, at least2500 ng*h/mL, at least 2550 ng*h/mL, at least 2600 ng*h/mL, at least2650 ng*h/mL, at least 2700 ng*h/mL, at least 2750 ng*h/mL, at least2800 ng*h/mL, at least 2850 ng*h/mL, at least 2900 ng*h/mL, at least2950 ng*h/mL, at least 3000 ng*h/mL, at least 3050 ng*h/mL, at least3100 ng*h/mL, at least 3150 ng*h/mL, at least 3200 ng*h/mL, at least3250 ng*h/mL, at least 3300 ng*h/mL, at least 3350 ng*h/mL, at least3400 ng*h/mL, at least 3450 ng*h/mL, at least 3500 ng*h/mL, at least3550 ng*h/mL, at least 3600 ng*h/mL, at least 3650 ng*h/mL, at least3700 ng*h/mL, at least 3750 ng*h/mL, at least 3800 ng*h/mL, at least3850 ng*h/mL, at least 3900 ng*h/mL, at least 3950 ng*h/mL, at least4000 ng*h/mL, at least 4050 ng*h/mL, at least 4100 ng*h/mL, at least4150 ng*h/mL, at least 4200 ng*h/mL, at least 4250 ng*h/mL, at least4300 ng*h/mL, at least 4350 ng*h/mL, at least 4400 ng*h/mL, at least4450 ng*h/mL, at least 4500 ng*h/mL, at least 4550 ng*h/mL, at least4600 ng*h/mL, at least 4650 ng*h/mL, at least 4700 ng*h/mL, at least4750 ng*h/mL, at least 4800 ng*h/mL, at least 4850 ng*h/mL, at least4900 ng*h/mL, at least 4950 ng*h/mL, at least 5000 ng*h/mL, at least5050 ng*h/mL, at least 5100 ng*h/mL, at least 5150 ng*h/mL, at least5200 ng*h/mL, at least 5250 ng*h/mL, at least 5300 ng*h/mL, at least5350 ng*h/mL, at least 5400 ng*h/mL, at least 5450 ng*h/mL, at least5500 ng*h/mL, at least 5550 ng*h/mL, at least 5600 ng*h/mL, at least5650 ng*h/mL, at least 5700 ng*h/mL, at least 5750 ng*h/mL, at least5800 ng*h/mL, at least 5850 ng*h/mL, at least 5900 ng*h/mL, at least5950 ng*h/mL, at least 6000 ng*h/mL, at least 6050 ng*h/mL, at least6100 ng*h/mL, at least 6150 ng*h/mL, at least 6200 ng*h/mL, at least6250 ng*h/mL, at least 6300 ng*h,/mL, at least 6350 ng*h/mL, at least6400 ng*h/mL, at least 6450 ng*h/mL, at least 6500 ng*h/mL, at least6550 ng*h/mL, at least 6600 ng*h/mL, at least 6650 ng*h/mL, at least6700 ng*h/mL, at least 6750 ng*h/mL, at least 6800 ng*h/mL, at least6850 ng*h/mL, at least 6900 ng*h/mL, at least 6950 ng*h/mL, at least7000 ng*h/mL, at least 7050 ng*h/mL, at least 7100 ng*h/mL, at least7150 ng*h/mL, at least 7200 ng*h/mL, at least 7250 ng*h/mL, at least7300 ng*h/mL, at least 7350 ng*h/mL, at least 7400 ng*h/mL, at least7450 ng*h/mL, at least 7500 ng*h/mL, at least 7550 ng*h/mL, at least7600 ng*h/mL, at least 7650 ng*h/mL, at least 7700 ng*h/mL, at least7750 ng*h/mL, at least 7800 ng*h/mL, at least 7850 ng*h/mL, at least7900 ng*h/mL, at least 7950 ng*h/mL, at least 8000 ng*h/mL, at least8050 ng*h/mL, at least 8100 ng*h/mL, at least 8150 ng*h/mL, at least8200 ng*h/mL, at least 8250 ng*h/mL, at least 8300 ng*h/mL, at least8350 ng*h/mL, at least 8400 ng*h/mL, at least 8450 ng*h/mL, at least8500 ng*h/mL, at least 8550 ng*h/mL, at least 8600 ng*h/mL, at least8650 ng*h/mL, at least 8700 ng*h/mL, at least 8750 ng*h/mL, at least8800 ng*h/mL, at least 8850 ng*h/mL, at least 8900 ng*h/mL, at least8950 ng*h/mL, at least 9000 ng*h/mL, at least 9050 ng*h/mL, at least9100 ng*h/mL, at least 9150 ng*h/mL, at least 9200 ng*h/mL, at least9250 ng*h/mL, at least 9300 ng*h/mL, at least 9350 ng*h/mL, at least9400 ng*h/mL, at least 9450 ng*h/mL, at least 9500 ng*h/mL, at least9550 ng*h/mL, at least 9600 ng*h/mL, at least 9650 ng*h/mL, at least9700 ng*h/mL, at least 9750 ng*h/mL, at least 9800 ng*h/mL, at least9850 ng*h/mL, at least 9900 ng*h/mL, at least 9950 ng*h/mL, or at least10000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol AUC_(4hr) or the patient population has amean AUC_(4hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least 1000 ng*h/mL and the patient is headachefree.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol AUC_(4hr) or the patient population has amean AUC_(4hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least 1000 ng*h/mL and the patient has experienceda reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol AUC_(4hr) or the patient population has amean AUC_(4hr) as set forth herein and the patient is no longerexperiencing its most bothersome symptom. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least 1000 ng*h/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hour after the administration the patienthas plasma fospropofol concentration (C_(4hr)) or the patient populationhas a mean C_(4hr) of 0 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has a plasma fospropofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) as set forth herein and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) of 0 ng/mL and the patient is headachefree.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) as set forth herein and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) of 0 ng/mL and the patient has experienceda reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) as set forth herein and the patient is nolonger experiencing its most bothersome symptom. In some embodiments,the MBS is nausea, photophobia, or phonophobia. In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma fospropofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) of 0 ng/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least at least 25 ng*h/mL, such as, for example, atleast 25 ng*h/mL, at least 50 ng*h/mL, at least 75 ng*h/mL, at least 100ng*h/mL, at least 125 ng*h/mL, at least 150 ng*h/mL, at least 175ng*h/mL, at least 200 ng*h/mL, at least 225 ng*h/mL, at least 250ng*h/mL, 275 ng*h/mL, at least 300 ng*h/mL, at least 325 ng*h/mL, atleast 350 ng*h/mL, at least 400 ng*h/mL, at least 425 ng*h/mL, at least450 ng*h/mL, at least 475 ng*h/mL, at least 500 ng*h/mL, at least 525ng*h/mL, at least 550 ng*h/mL, at least 575 ng*h/mL, at least 600ng*h/mL, at least 625 ng*h/mL, at least 650 ng*h/mL, at least 675ng*h/mL, at least 700 ng*h/mL, at least 725 ng*h/mL, at least 750ng*h/mL, at least 775 ng*h/mL, at least 800 ng*h/mL, at least 825ng*h/mL, at least 850 ng*h/mL, at least 875 ng*h/mL, at least 900ng*h/mL, at least 925 ng*h/mL, at least 950 ng*h/mL, at least 975ng*h/mL, or at least 1000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol AUC_(1hr) or the patient population has a meanAUC_(1hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least 250 ng*h/mL and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol AUC_(1hr) or the patient population has a meanAUC_(1hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least 50 ng*h/mL and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol AUC_(1hr) or the patient population has a meanAUC_(1hr) as set forth herein and the patient is no longer experiencingits most bothersome symptom. In some embodiments, the MBS is nausea,photophobia, or phonophobia. In some embodiments, the MBS is nausea,photophobia, or phonophobia. In some embodiments, the MBS is nausea. Insome embodiments, the MBS is photophobia. In some embodiments, the MBSis phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol AUC_(1hr) or the patient population has a meanAUC_(1hr) of at least 50 ng*h/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) of at least 25 ng/mL, such as, for example, at least25 ng/mL, at least 50 ng/mL, at least 75 ng/mL, at least 100 ng/mL, atleast 125 ng/mL, at least 150 ng/mL, at least 175 ng/mL, at least 200ng/mL, at least 225 ng/mL, at least 250 ng/mL, 275 ng/mL, at least 300ng/mL, at least 325 ng/mL, at least 350 ng/mL, at least 400 ng/mL, atleast 425 ng/mL, at least 450 ng/mL, at least 475 ng/mL, at least 500ng/mL, at least 525 ng/mL, at least 550 ng/mL, at least 575 ng/mL, atleast 600 ng/mL, at least 625 ng/mL, at least 650 ng/mL, at least 675ng/mL, at least 700 ng/mL, at least 725 ng/mL, at least 750 ng/mL, atleast 775 ng/mL, at least 800 ng/mL, at least 825 ng/mL, at least 850ng/mL, at least 875 ng/mL, at least 900 ng/mL, at least 925 ng/mL, atleast 950 ng/mL, at least 975 ng/mL, or at least 1000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas a plasma propofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) of at least 500 ng/mL and the patient is headachefree.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) of at least 90 ng/mL and the patient has experienceda reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) as set forth herein and the patient is no longerexperiencing its most bothersome symptom. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 1 hour after the administration the patienthas plasma propofol concentration (C_(1hr)) or the patient populationhas a mean C_(1hr) of at least 90 ng/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least at least 25 ng*h/mL, such as, for example, atleast 25 ng*h/mL, at least 50 ng*h/mL, at least 75 ng*h/mL, at least 100ng*h/mL, at least 125 ng*h/mL, at least 150 ng*h/mL, at least 175ng*h/mL, at least 200 ng*h/mL, at least 225 ng*h/mL, at least 250ng*h/mL, 275 ng*h/mL, at least 300 ng*h/mL, at least 325 ng*h/mL, atleast 350 ng*h/mL, at least 400 ng*h/mL, at least 425 ng*h/mL, at least450 ng*h/mL, at least 475 ng*h/mL, at least 500 ng*h/mL, at least 525ng*h/mL, at least 550 ng*h/mL, at least 575 ng*h/mL, at least 600ng*h/mL, at least 625 ng*h/mL, at least 650 ng*h/mL, at least 675ng*h/mL, at least 700 ng*h/mL, at least 725 ng*h/mL, at least 750ng*h/mL, at least 775 ng*h/mL, at least 800 ng*h/mL, at least 825ng*h/mL, at least 850 ng*h/mL, at least 875 ng*h/mL, at least 900ng*h/mL, at least 925 ng*h/mL, at least 950 ng*h/mL, at least 975ng*h/mL, or at least 1000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol AUC_(2hr) or the patient population has amean AUC_(2hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least 100 ng*h/mL and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol AUC_(2hr) or the patient population has amean AUC_(2hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least 90 ng*h/mL and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol AUC_(2hr) or the patient population has amean AUC_(2hr) as set forth herein and the patient is no longerexperiencing its most bothersome symptom. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol AUC_(2hr) or the patient population has amean AUC_(2hr) of at least 40 ng*h/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) of at least 25 ng/mL, such as, forexample, at least 25 ng/mL, at least 50 ng/mL, at least 75 ng/mL, atleast 100 ng/mL, at least 125 ng/mL, at least 150 ng/mL, at least 175ng/mL, at least 200 ng/mL, at least 225 ng/mL, at least 250 ng/mL, 275ng/mL, at least 300 ng/mL, at least 325 ng/mL, at least 350 ng/mL, atleast 400 ng/mL, at least 425 ng/mL, at least 450 ng/mL, at least 475ng/mL, at least 500 ng/mL, at least 525 ng/mL, at least 550 ng/mL, atleast 575 ng/mL, at least 600 ng/mL, at least 625 ng/mL, at least 650ng/mL, at least 675 ng/mL, at least 700 ng/mL, at least 725 ng/mL, atleast 750 ng/mL, at least 775 ng/mL, at least 800 ng/mL, at least 825ng/mL, at least 850 ng/mL, at least 875 ng/mL, at least 900 ng/mL, atleast 925 ng/mL, at least 950 ng/mL, at least 975 ng/mL, or at least1000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hour after the administration the patienthas a plasma propofol concentration (C_(2hr)) or the patient populationhas a mean C_(2hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) of at least 40 ng/mL and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hour after the administration the patienthas plasma propofol concentration (C_(2hr)) or the patient populationhas a mean C_(2hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) of at least 40 ng/mL and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) as set forth herein and the patient is nolonger experiencing its most bothersome symptom. In some embodiments,the MBS is nausea, photophobia, or phonophobia. In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 2 hours after the administration thepatient has plasma propofol concentration (C_(2hr)) or the patientpopulation has a mean C_(2hr) of at least 20 ng/mL and the patient is nolonger experiencing its most bothersome symptom (MBS). In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least at least 25 ng*h/mL, such as, for example, atleast 25 ng*h/mL, at least 50 ng*h/mL, at least 75 ng*h/mL, at least 100ng*h/mL, at least 125 ng*h/mL, at least 150 ng*h/mL, at least 175ng*h/mL, at least 200 ng*h/mL, at least 225 ng*h/mL, at least 250ng*h/mL, 275 ng*h/mL, at least 300 ng*h/mL, at least 325 ng*h/mL, atleast 350 ng*h/mL, at least 400 ng*h/mL, at least 425 ng*h/mL, at least450 ng*h/mL, at least 475 ng*h/mL, at least 500 ng*h/mL, at least 525ng*h/mL, at least 550 ng*h/mL, at least 575 ng*h/mL, at least 600ng*h/mL, at least 625 ng*h/mL, at least 650 ng*h/mL, at least 675ng*h/mL, at least 700 ng*h/mL, at least 725 ng*h/mL, at least 750ng*h/mL, at least 775 ng*h/mL, at least 800 ng*h/mL, at least 825ng*h/mL, at least 850 ng*h/mL, at least 875 ng*h/mL, at least 900ng*h/mL, at least 925 ng*h/mL, at least 950 ng*h/mL, at least 975ng*h/mL, or at least 1000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol AUC_(4hr) or the patient population has amean AUC_(4hr) as set forth herein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least 150 ng*h/mL and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol AUC_(4hr) or the patient population has amean AUC_(4hr) as set forth herein and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least 150 ng*h/mL and the patient has experienced areduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol AUC_(4hr) or the patient population has amean AUC_(4hr) as set forth herein and the patient is no longerexperiencing its most bothersome symptom. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol AUC_(4hr) or the patient population has amean AUC_(4hr) of at least 100 ng*h/mL and the patient is no longerexperiencing its most bothersome symptom (MBS). In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea, photophobia, or phonophobia. In some embodiments, the MBS isnausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hour after the administration the patienthas plasma propofol concentration (C_(4hr)) or the patient populationhas a mean C_(4hr) of at least 5 ng/mL, such as, for example, at least 5ng/mL, at least 10 ng/mL, at least 15 ng/mL, at least 20 ng/mL, at least25 ng/mL, at least 50 ng/mL, at least 75 ng/mL, at least 100 ng/mL, atleast 125 ng/mL, at least 150 ng/mL, at least 175 ng/mL, at least 200ng/mL, at least 225 ng/mL, at least 250 ng/mL, 275 ng/mL, at least 300ng/mL, at least 325 ng/mL, at least 350 ng/mL, at least 400 ng/mL, atleast 425 ng/mL, at least 450 ng/mL, at least 475 ng/mL, at least 500ng/mL, at least 525 ng/mL, at least 550 ng/mL, at least 575 ng/mL, atleast 600 ng/mL, at least 625 ng/mL, at least 650 ng/mL, at least 675ng/mL, at least 700 ng/mL, at least 725 ng/mL, at least 750 ng/mL, atleast 775 ng/mL, at least 800 ng/mL, at least 825 ng/mL, at least 850ng/mL, at least 875 ng/mL, at least 900 ng/mL, at least 925 ng/mL, atleast 950 ng/mL, at least 975 ng/mL, or at least 1000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has a plasma propofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) as set forth herein and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) of at least 10 ng/mL and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) as set forth herein and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) of at least 10 ng/mL and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) as set forth herein and the patient is nolonger experiencing its most bothersome symptom. In some embodiments,the MBS is nausea, photophobia, or phonophobia. In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, wherein at 4 hours after the administration thepatient has plasma propofol concentration (C_(4hr)) or the patientpopulation has a mean C_(4hr) of at least 10 ng/mL and the patient is nolonger experiencing its most bothersome symptom (MBS). In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the methods described herein are directed to treating adisease or disorder in a subject in need thereof.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is migraine, acute repetitiveseizures, seizure clusters, neuropathic pain, postherpetic neuralgia,traumatic brain injury, Alzheimer's disease, epilepsy, anxiety, fragileX syndrome, post-traumatic stress disorder, lysosomal storage disorders(Niemann-Pick type C disease), depression (including post-partumdepression), premenstrual dysphoric disorder, alcohol craving, orsmoking cessation.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is migraine.

In some aspects, the disclosure is directed to methods of treatingmigraine.

In some embodiments, the subject's migraine is migraine with aura.

In other embodiments, the subject's migraine is migraine without aura.

In other embodiments, the subject's migraine is cluster headache.

In other embodiments, the subject's migraine is intractable migraine.

In some embodiments, the patient's migraine is refractory migraine. Insome embodiments of the disclosed methods, the subject's refractorymigraine may fail to respond to CGRP inhibitors, and is referred to asCGRP inhibitor-refractory migraine.

In some embodiments, the subject's CGRP-inhibitor refractory migrainefails to respond to gepant treatment, and is referred to asgepant-refractory migraine. In other embodiments, the subject'sCGRP-inhibitor refractory migraine fails to respond to anti-CGRPantibodies, and is referred to as anti-CGRP antibody-refractorymigraine.

In other embodiments, the subject's refractory migraine may fail torespond to triptans, and is referred to as triptan-refractory migraine.

In other embodiments, the subject's refractory migraine may fail torespond to NSAIDs and is referred to as NSAID-refractory migraine.

In other embodiments, the subject's refractory migraine may fail torespond to dihydroegotamine (DHE) and is referred to as DHE-refractorymigraine.

In some embodiments of the methods of the disclosure, the fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,may be administered in combination with other drugs that are used totreat migraine.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is epilepsy.

In some embodiments of the disclosed methods of treating a disease ordisorder, the disease or disorder is tremor. In some embodiments, thetremor is essential tremor or Parkinsonian tremor (tremor in personswith Parkinson's disease). In other embodiments, the tremor isorthostatic tremor, primary writing tremor, cerebellar tremor, rubraltremor, neuropathic tremor or dystonic tremor.

In some embodiments of the methods of the disclosure, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in areduction of the patient's migraine pain.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by change in the patient's rating of the severity of thepain following administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by change in the patient's rating of the pain from severeprior to administration of fospropofol, to no pain followingadministration of fospropofol, or a pharmaceutically acceptable saltthereof.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by change in the patient's rating of the pain from severeprior to administration of fospropofol, to mild following administrationof fospropofol, or a pharmaceutically acceptable salt thereof.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by change in the patient's rating of the pain from severeprior to administration of fospropofol, to moderate followingadministration of fospropofol, or a pharmaceutically acceptable saltthereof.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by change in the patient's rating of the pain from moderateprior to administration of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, to no pain followingadministration of fospropofol.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by change in the patient's rating of the pain from moderateprior to administration of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, to mild followingadministration of fospropofol.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by change in the patient's rating of the pain from mildprior to administration of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, to no pain followingadministration of fospropofol.

In some embodiments, the reduction of the patient's migraine pain isdemonstrated by a reduction of three points in a 4 point Likert scale.The term “Likert scale” as used herein, refers generally to aquestionnaire—based rating scale in which the patient is asked to ratethe severity of the pain on a scale of, for example, 0-3, wherein0=none, 1=mild, 2=moderate, 3=severe.

In other embodiments, the reduction of the patient's migraine pain isdemonstrated by a reduction of at least two points in a 4 point Likertscale.

In other embodiments, the reduction of the patient's migraine pain isdemonstrated by a reduction of at least one point in a 4 point Likertscale.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a reduction of the patient's migraine painfrom severe to moderate on a 4-point Likert scale in which the 4 pointsare None, Mild, Moderate, Severe.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a reduction of the patient's migraine painfrom severe to mild on a 4-point Likert scale in which the 4 points areNone, Mild, Moderate, Severe.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a reduction of the patient's migraine painfrom severe to none on a 4-point Likert scale in which the 4 points areNone, Mild, Moderate, Severe.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a reduction of the patient's migraine painfrom moderate to mild on a 4-point Likert scale in which the 4 pointsare None, Mild, Moderate, Severe.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a reduction of the patient's migraine painfrom moderate to none on a 4-point Likert scale in which the 4 pointsare None, Mild, Moderate, Severe.

In some embodiments, administering an effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, inone or more doses, results in a reduction of the patient's migraine painfrom mild to none on a 4-point Likert scale in which the 4 points areNone, Mild, Moderate, Severe.

In some embodiments of the disclosed methods, administering an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in areduction in the patient's headache pain, and the elimination of thepatient's bothersome symptom, within 2 hours.

In some embodiments of the disclosed methods, administering an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in areduction in the patient's headache pain, and the elimination of thepatient's most bothersome symptom, within 2 hours.

In some embodiments of the disclosed methods, administering an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in areduction in the patient's headache pain, and the elimination of thepatient's nausea, within 2 hours.

In some embodiments of the disclosed methods, administering an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in areduction in the patient's headache pain, and the elimination of thepatient's photophobia, within 2 hours.

In some embodiments of the disclosed methods, administering an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in areduction in the patient's headache pain, and the elimination of thepatient's phonophobia, within 2 hours.

In other embodiments of the disclosed methods, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in anelimination of the patient's headache pain, and the elimination of thepatient's most bothersome symptom, within 2 hours.

In other embodiments of the disclosed methods, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in anelimination of the patient's headache pain, and the elimination of thepatient's most bothersome symptom, within 2 hours.

In other embodiments of the disclosed methods, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in anelimination of the patient's headache pain, and the elimination of thepatient's nausea, within 2 hours.

In other embodiments of the disclosed methods, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in anelimination of the patient's headache pain, and the elimination of thepatient's photophobia, within 2 hours.

In other embodiments of the disclosed methods, administering aneffective amount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, in one or more doses, results in anelimination of the patient's headache pain, and the elimination of thepatient's phonophobia, within 2 hours.

In some aspects of the disclosed methods, the reduction in the patient'smigraine pain occurs within 5-240 minutes, for example, 10-240 minutesof administration of fospropofol, or a pharmaceutically acceptable saltthereof.

In some embodiments, the reduction in the patient-s migraine pain occurswithin 5-15 minutes, for example, 10-15 minutes of administration offospropofol, or a pharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 5-30 minutes, for example, 10-30 minutes of administration offospropofol, or a pharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 5-60 minutes, for example, 10-60 minutes of administration offospropofol, or a pharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 5-120 minutes, for example, 10-120 minutes of administration offospropofol, or a pharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 120 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 30 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 60 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 90 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 120 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 3 hour of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 4 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 6 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 12 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 24 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the reduction in the patient's migraine pain occurswithin 48 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some aspects of the disclosed methods, a patient whose migraine painwas eliminated following administration of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,remains free of migraine pain for at least 12 hours.

In some aspects of the disclosed methods, a patient whose migraine painwas eliminated following administration of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof,remains free of migraine pain for at least 24 hours.

In some embodiments, a patient whose migraine pain was eliminatedfollowing administration of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, remains free of migraine painfor at least 48 hours.

In some embodiments, a patient whose migraine pain was eliminatedfollowing administration of fospropofol, a pharmaceutically acceptablesalt of fospropofol, or mixtures thereof, remains free of migraine painfor at least 72 hours.

In some aspects of the disclosed methods, administration of an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, to a patient whose migraine symptomsinclude nausea/vomitting results in elimination of the patient'snausea/vomitting.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 30 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 60 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 90 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 120 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 3 hour of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 4 hours of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 6 hours of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 12 hours of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 24 hours of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's nausea/vomittingoccurs within 48 hours of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includenausea/vomitting results in reduction of nausea/vomitting of at least50% from baseline as measured by the patient's rating.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includenausea/vomitting results in reduction of nausea/vomitting of at least93% from baseline as measured by the patient's rating.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includenausea/vomitting results in reduction of nausea/vomitting of less than90% from baseline as measured by the patient's rating.

In some aspects of the disclosed methods, administration of an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, to a patient whose migraine symptomsinclude photophobia results in elimination of the patient's photophobia.In some embodiments, the elimination of the patient's photophobia occurswithin 30 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 60 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 90 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 120 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 3 hour of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 4 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 6 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 12 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 24 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's photophobia occurswithin 48 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includephotophobia results in reduction of photophobia of at least 50% asmeasured by the patient's rating.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includephotophobia results in reduction of photophobia of at least 80% asmeasured by the patient's rating.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includephotophobia results in reduction of photophobia of less than 75% asmeasured by the patient's rating.

In some aspects of the disclosed methods, administration of an effectiveamount of fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, to a patient whose migraine symptomsinclude phonophobia results in elimination of the patient's phonophobia.

In some embodiments, the elimination of the patient's phonophobia occurswithin 30 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 60 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 90 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 120 minutes of administration of fospropofol, or apharmaceutically acceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 3 hour of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 4 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 6 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 12 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 24 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the elimination of the patient's phonophobia occurswithin 48 hours of administration of fospropofol, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includephonophobia results in reduction of phonophobia of at least 50% asmeasured by the patient's rating.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includephonophobia results in reduction of phonophobia of at least 80% asmeasured by the patient's rating.

In some embodiments, administration of an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to a patient whose migraine symptoms includephonophobia results in reduction of phonophobia of less than 75% asmeasured by the patient's rating.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in no clinically meaningful risk of apnea.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in no clinically meaningful risk of hypoxemia

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of hypotension of less than 2%. In someembodiments, administering to the patient an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, in one or more doses, results in a risk of hypotensionof less than 10%.

In some embodiments, administering to the patient an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, in one or more doses, results in a risk of hypotensionof greater than 5%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in no clinically meaningful risk of developingunresponsiveness to vigorous tactile or painful stimulation as assessedusing the Modified Observer's Assessment of Alertness (OAA/S) Scale.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of paresthesia of less than 20%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of paresthesia of less than 40%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of paresthesia of less than 60%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of paresthesia of less than 80%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of developing cough of less than 10%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of pruritus of less than 10%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of euphoria of less than 25%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of seeking behavior of less than 5%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of excessive somnolence of less than 15%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of excessive somnolence less than 20%.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of chest tightness of less than 2%.

In some embodiments, administering to the patient an effective amount offospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, in one or more doses, results in no clinicallymeaningful risk of chest tightness.

In some embodiments of the disclosed methods, administering to thepatient an effective amount of fospropofol, a pharmaceuticallyacceptable salt of fospropofol, or mixtures thereof, in one or moredoses, results in a risk of chest tightness greater than 5%.

PHARMACEUTICAL COMPOSITIONS

In some aspects, the disclosure is directed to pharmaceuticalcompositions comprising fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof, and a pharmaceutically acceptableexcipient.

In some embodiments, the pharmaceutical composition is a solid.

In other embodiments, the pharmaceutical composition is a liquid.

In other embodiments, the pharmaceutical composition is a suspension.

In other embodiments, the pharmaceutical composition is a paste.

The pharmaceutical compositions of the present disclosure may take anyphysical form suitable for the mode of administration.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule (gelatin or non-gelatin), enteric capsules, cachets,tablets, beads, or powders.

In some embodiments, the physical form of the pharmaceutical compositionis coated beads.

In other embodiments, the physical form of the pharmaceuticalcomposition is tablets.

In some embodiments, the physical form of the pharmaceutical compositionis coated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis enteric coated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis multilayer tablets.

In some embodiments, the physical form of the pharmaceutical compositionis multilayer coated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis coated multilayer uncoated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis a tablet within a tablet.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule containing pellets or beads.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule containing pellets or beads, wherein the pellets or beadsare heterogenous with respect to release of fospropofol.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule containing tablets, wherein the tablets are heterogenouswith respect to release of fospropofol.

In other embodiments, the physical form of the pharmaceuticalcomposition is a gel, water soluble jellies, creams, lotions,suspensions, foams, powders, slurries, ointments, solutions, oils,pastes, suppositories, sprays, or emulsions.

In some embodiments, the physical form of the pharmaceutical compositionis a controlled release dosage form. As used herein, the term“controlled release dosage form” refers to a dosage form that releasesthe encompassed fospropofol over an extended period of time.

In some embodiments, the physical form of the pharmaceutical compositionis a modified-release dosage form.

In some aspects, the pharmaceutical compositions of the disclosurecomprises a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutically acceptable excipient may bewater, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, starches, sugars, micro-crystalline cellulose,surfactants, polymers, diluents, granulating agents, lubricants,binders, fillers, and disintegrants.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,dicalcium phosphate, hydroxypropyl methyl cellulose, microcrystallinecellulose, and mixtures thereof.

Fillers for use in the pharmaceutical compositions and dosage formsdisclosed herein include, but are not limited to, talc, calciumcarbonate (e.g., granules or powder), microcrystalline cellulose,powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol,starch, dicalcium phosphate, pre-gelatinized starch, and mixturesthereof.

Disintegrants that can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums ormixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof.

In some embodiments, the solid pharmaceutical dosage form is uncoated orcoated to delay disintegration and absorption in the gastrointestinaltract. For example, a time delay material such as glyceryl monostearateor glyceryl distearate can be employed.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, ionic surfactants, andmixtures thereof.

Suitable ionic surfactants include, but are not limited to,alkylammonium salts; fusidic acid salts; fatty acid derivatives of aminoacids, oligopeptides, and polypeptides; glyceride derivatives of aminoacids, oligopeptides, and polypeptides; lecithins and hydrogenatedlecithins; lysolecithins and hydrogenated lysolecithins; phospholipidsand derivatives thereof; lysophospholipids and derivatives thereof;camitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof, lecithins, lysolecithin, phospholipids,lysophospholipids and derivatives thereof; carnitine fatty acid estersalts; salts of alkylsulfates; fatty acid salts; sodium docusate;acylactylates; mono- and di-acetylated tartaric acid esters of mono- anddi-glycerides; succinylated mono- and di-glycerides; citric acid estersof mono- and di-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carntines, palmitoyl carnitines, myristoyl carnitines, and saltsand mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene gly col glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrosemono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof.

Solubilizers include, but are not limited to, the following: alcoholsand polyols, such as ethanol, isopropanol, butanol, benzyl alcohol,ethylene glycol, propylene glycol, butanediols and isomers thereof,glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethylisosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol,hydroxypropyl methylcellulose and other cellulose derivatives,cyclodextrins and cyclodextrin derivatives; ethers of polyethyleneglycols having an average molecular weight of about 200 to about 6000,such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxyPEG; amides and other nitrogen-containing compounds such as2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide and polyvinylpyrrolidone; esters such as ethylpropionate, tributylcitrate, acetyl triethylcitrate, acetyl tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,triacetin, propylene glycol monoacetate, propylene glycol diacetate,ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof,β-butyrolactone and isomers thereof, and other solubilizers known in theart, such as dimethyl acetamide, dimethyl isosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycol monoethyl ether, andwater.

Release modifiers may include coatings or matrix materials.

Release modifying coatings include but are not limited to polymercoating materials, such as cellulose acetate phthalate, celluloseacetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinylacetate phthalate, ammonio methacrylate copolymers such as those soldunder the Trade Mark Eudragit® RS and RL, poly acrylic acid and polyacrylate and methacrylate copolymers such as those sold under the TradeMark Eudragite S and L, polyvinyl acetaldiethylamino acetate,hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels andgel-forming materials, such as carboxyvinyl polymers, sodium alginate,sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin,starch, and cellulose based cross-linked polymers—in which the degree ofcrosslinking is low so as to facilitate adsorption of water andexpansion of the polymer matrix, hydoxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer(Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gumarabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers)poly(hydroxyalkyl methacrylate) (m. wt. ^(˜)5 k-5,000 k),polyvinylpyrrolidone (m. wt. ^(˜)10 k-360 k), anionic and cationichydrogels, polyvinyl alcohol having a low acetate residual, a swellablemixture of agar and carboxymethyl cellulose, copolymers of maleicanhydride and styrene, ethylene, propylene or isobutylene, pectin (m.wt. ^(˜)30 k-300 k), polysaccharides such as agar, acacia, karaya,tragacanth, algins and guar, polyacrylamides, Polyox® polyethyleneoxides (m. wt. ^(˜)100 k-5.000 k), AquaKeep® acrylate polymers, diestersof polyglucan, crosslinked polyvinyl alcohol and polyN-vinyl-2-pyrrolidone, sodium starch glucolate (e.g. Explotab®; EdwardMandell C. Ltd.); hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, polyethyleneoxides (e.g. Polyox®, Union Carbide), methyl ethyl cellulose,ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan,polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerolfatty acid esters, polyacrylamide, polyacrylic acid, copolymers ofmethacrylic acid or methacrylic acid (e.g. Eudragit®, Rohm and Haas),other acrylic acid derivatives, sorbitan esters, natural gums,lecithins, pectin, alginates, ammonia alginate, sodium, calcium,potassium alginates, propylene glycol alginate, agar, and gums such asarabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan,scleroglucan and mixtures and blends thereof. As will be appreciated bythe person skilled in the art, excipients such as plasticisers,lubricants, solvents and the like may be added to the coating. Suitableplasticisers include for example acetylated monoglycerides; butylphthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethylphthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol;triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetylmonoglyceride; polyethylene glycols; castor oil; triethyl citrate;polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate,acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctylazelate, epoxidised tallate, triisoctyl trimellitate, diethylhexylphthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decylphthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate,tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexylsebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

Release-modifying matrix materials include hydrophilic polymers,hydrophobic polymers and mixtures thereof, dicalcium phosphate,microcrytalline cellulose, sodium carboxymethylcellulose,hydoxyalkylcelluloses such as hydroxypropylmethylcellulose andhydroxypropylcellulose, polyethylene oxide, alkylcelluloses such asmethylcellulose and ethylcellulose, polyethylene glycol,polyvinylpyrrolidone, cellulose actetate, cellulose acetate butyrate,cellulose actetate phthalate, cellulose acteate trimellitate,polyvinylacetate phthalate, polyalkylmethacrylates, polyvinyl acetate,Poly(2-hydroxy ethyl methacrylate), Poly(N-vinyl pyrrolidone),Poly(methyl methacrylate), Poly(vinyl alcohol), Poly(acrylic acid),Polyacrylamide, Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol),Poly(methacrylic acid), Polylactides (PLA), Polyglycolides (PGA),Poly(lactide-co-glycolides) (PLGA), Polyanhydrides, and Polyorthoesters,and mixture thereof.

In some aspects, pharmaceutical compositions of the disclosure comprisean effective amount of fospropofol, a pharmaceutically acceptable saltof fospropofol, or mixtures thereof.

In some embodiments of the pharmaceutical compositions of the disclosurecomprise an effective amount of fospropofol.

In other embodiments, the pharmaceutical compositions of the disclosurecomprise an effective amount of a pharmaceutically acceptable salt offospropofol.

In some embodiments, pharmaceutical compositions of the disclosurecomprise fospropofol disodium.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise an effective amount of a mixture of fospropofol and apharmaceutically acceptable salt thereof. Thus, in some embodiments, thepharmaceutical compositions of the disclosure comprise an effectiveamount of fospropofol and fospropofol disodium.

In other embodiments, the pharmaceutical compositions of the disclosurecomprise an effective amount of a mixture of pharmaceutically acceptablesalts. In some embodiments, the pharmaceutical compositions of thedisclosure comprise an effective amount of a mixture of fospropofoldisodium and a second pharmaceutically acceptable fospropofol salt.

In some aspects, the pharmaceutical compositions of the disclosurecomprise an effective amount of fospropofol, a pharmaceuticallyacceptable salt of phospropofol, or mixtures thereof.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 50-4800 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg,350 mg, 400 mg, 450 mg. 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg,800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg, 3100 mg, 3150 mg, 3200mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, or4800 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 50-1000 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg,350 mg, 400 mg, 450 mg, 500 mg, 550 mg. 600 mg, 650 mg, 700 mg, 750 mg,800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 50-750 mg (on a fospropofol basis),for example, an amount that is about (i.e., the specified number±10%)any one of 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg,250 mg. 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg,475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg,700 mg, 725 mg, or 750 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 75-1500 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg,525 mg, 600 mg, 675 mg, 750 mg, 825 mg, 900 mg, 975 mg, 1050 mg, 1125mg, 1200 mg, 1275 mg, 1350 mg, 1425 mg, or 1500 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 100-4800 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg,850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg,1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg,1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg,2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg,2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg,2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg, 3100 mg, 3150 mg, 3200 mg,3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg,3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg,4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg,4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, or 4800mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 100-3600 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg,850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg,1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg,1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg,2050 mg, 2100 mg. 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg,2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg,2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg, 3100 mg, 3150 mg, 3200 mg,3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, or 3600mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 100-3200 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg. 750 mg, 800 mg,850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg,1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg,1650 mg. 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg,2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg,2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg,2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg, 3100 mg, 3150 mg, or 3200mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-2400 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg. 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg. 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg,1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg,2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, or 2400 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-2300 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg.1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg,2150 mg, 2200 mg, 2250 mg, or 2300 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-2200 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg,1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg,2150 mg, or 2200 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-2100 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg,1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, or 2100mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-2000 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg,1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1900 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg,1750 mg, 1800 mg, 1850 mg, or 1900 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1800 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg. 750 mg, 800 mg. 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg,1750 mg, or 1800 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1700 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg. 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, or 1700mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1600 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1600 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1500 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, 1400 mg, 1450 mg, or 1500 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1400 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg,1350 mg, or 1400 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1300 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, or 1300mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1200 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1100 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg,950 mg, 1000 mg, 1050 mg, or 1100 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-1000 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg. 750 mg, 800 mg, 850 mg, 900 mg,950 mg, or 1000 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-900 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-800 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-700 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, 600 mg, 650 mg, or 700 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-600 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg,500 mg, 550 mg, or 600 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-500 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg. 300 mg, 350 mg, 400 mg, 450 mg,or 500 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-400 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200-300 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 200 mg, 250 mg, or 300 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-2400 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300mg, 2350 mg, or 2400 mg.

In some embodiments, the effective amount of fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, isIn some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-2000 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900mg, 1950 mg, or 2000 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-1600 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500mg, 1550 mg, or 1600 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-1200 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100mg, 1150 mg, or 1200 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-1200 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100mg, 1150 mg, or 1200 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-1000 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-800 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg,700 mg, 750 mg, or 800 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400-600 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 600-1200 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 600 mg, 650 mg. 700 mg, 750 mg, 800 mg, 850 mg,900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 800-1200 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 800 mg, 850 mg. 900 mg, 950 mg, 1000 mg, 1050 mg,1100 mg, 1150 mg, or 1200 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 1000-2000 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 1000-1600 mg (on a fospropofolbasis) delivered perorally, for example, an amount that is about (i.e.,the specified number±10%) any one of 1000 mg, 1050 mg, 1100 mg, 1150 mg,1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,or 1600 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 1200-2000 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850mg, 1900 mg, 1950 mg, or 2000 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 1200-1800 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, or 1800 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 1600-2400 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250mg, 2300 mg, 2350 mg, or 2400 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 1800-2400 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, or 2400 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 2000-2400 mg (on a fospropofolbasis), for example, an amount that is about (i.e., the specifiednumber±10%) any one of 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250mg, 2300 mg, 2350 mg, or 2400 mg.

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 50 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 100 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 125 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 150 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 175 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 200 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 225 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 250 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 275 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 300 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 325 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 350 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 375 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 400 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 425 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 450 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 475 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 500 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 525 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 550 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 575 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 600 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 625 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 650 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 675 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 700 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 725 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 750 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 775 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 800 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 825 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 850 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 875 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 900 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 925 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 950 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 975 mg (on a fospropofol basis).

In some embodiments, the pharmaceutical compositions of the disclosurecomprise fospropofol, a pharmaceutically acceptable salt of fospropofol,or mixtures thereof, in an amount of 1000 mg (on a fospropofol basis).

In some aspects of the disclosure, the pharmaceutical compositions ofthe disclosure have specific release characteristics.

In some embodiments, the pharmaceutical compositions of the disclosure,20% to 80% by weight of the pharmaceutical composition dissolves within30 minutes when suspended in 0.1 N HCl.

In some embodiments, the pharmaceutical compositions of the disclosure,20% to 80% by weight of said solid pharmaceutical composition dissolveswithin 30 minutes when suspended in pH 4.5 buffer.

The pharmaceutical compositions of the disclosure may be used inperforming the methods of treatment of the disclosure.

In some aspects, the pharmaceutical compositions of the disclosure, whenadministered to a patient, produce specific pharmacokinetic profiles.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 200-4000 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL,850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL,1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL,1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL,1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 2000 ng/mL, 2050 ng/mL,2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL,2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL,2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL,3000 ng/mL, 3050 ng/mL, 3100 ng/mL, 3150 ng/mL, 3200 ng/mL, 3250 ng/mL,3300 ng/mL, 3350 ng/mL, 3400 ng/mL, 3450 ng/mL, 3500 ng/mL, 3550 ng/mL,3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL,3900 ng/mL, 3950 ng/mL, or 4000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 200-1600 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL,850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL,1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL,1450 ng/mL, 1500 ng/mL, 1550 ng/mL, or 1600 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 200-1200 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL,850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL,1150 ng/mL, or 1200 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 200-1000 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL,850 ng/mL, 900 ng/mL, 950 ng/mL, or 1000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 200-800 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, or 800ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 200-600 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, or 600 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 200-400 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, or 400 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of at least 50-500 ng/mL, for example, aCmax or mean Cmax that is about (i.e., the specified number±10%) any oneof 50 ng/mL, 100 ng/mL, 150 ng/mL, 200 ng/mL, 250 ng/mL, 300 ng/mL, 350ng/mL, 400 ng/mL, 450 ng/mL, or 500 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 5000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 4000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 3000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 2000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax of propofol of no greater than 1600 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 1200 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax of propofol of no greater than 1000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 800 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 600 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 500 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 400 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 200 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of propofol of no greater than 100 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of at least 800-18000 ng/mL, forexample, a Cmax or mean Cmax that is about (i.e., the specifiednumber±10%) any one of 800 ng/mL, 850 ng/mL, 900 ng/mL, 950 ng/mL, 1000ng/mL, 1050 ng/mL, 1100 ng/mL, 1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300ng/mL, 1350 ng/mL, 1400 ng/mL, 1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600ng/mL, 1650 ng/mL, 1700 ng/mL, 1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900ng/mL, 1950 ng/mL, 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL, 2200ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL, 2500ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL, 2800ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL, 3550ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850ng/mL, 3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL, 4150ng/mL, 4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL, 4450ng/mL, 4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL, 4750ng/mL, 4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL, 5050ng/mL, 5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL, 5350ng/mL, 5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL, 5650ng/mL, 5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL, 5950ng/mL, 6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL, 6250ng/mL, 6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL, 6550ng/mL, 6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL, 6850ng/mL, 6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL, 7150ng/mL, 7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL, 7450ng/mL, 7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL, 7750ng/mL, 7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL, 8050ng/mL, 8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL, 8350ng/mL, 8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL, 8650ng/mL, 8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL, 8950ng/mL, 9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL, 9250ng/mL, 9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL, 9550ng/mL, 9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL, 9950ng/mL, 9900 ng/mL, 9950 ng/mL, 10000 ng/mL, 10050 ng/mL, 10100 ng/mL,10150 ng/mL, 10200 ng/mL, 10250 ng/mL, 10300 ng/mL, 10350 ng/mL, 10400ng/mL, 10450 ng/mL, 10500 ng/mL, 10550 ng/mL, 10600 ng/mL, 10650 ng/mL,10700 ng/mL, 10750 ng/mL, 1000 ng/mL, 101050 ng/mL, 10900 ng/mL, 10950ng/mL, 11000 ng/mL, 11050 ng/mL, 11100 ng/mL, 11150 ng/mL, 11200 ng/mL,11250 ng/mL, 11300 ng/mL, 11350 ng/mL, 11400 ng/mL, 11450 ng/mL, 11500ng/mL, 11550 ng/mL, 11600 ng/mL, 11650 ng/mL, 11700 ng/mL, 11750 ng/mL,1100 ng/mL, 111150 ng/mL, 11900 ng/mL, 11950 ng/mL, 12000 ng/mL, 12050ng/mL, 12100 ng/mL, 12150 ng/mL, 12200 ng/mL, 12250 ng/mL, 12300 ng/mL,12350 ng/mL, 12400 ng/mL, 12450 ng/mL, 12500 ng/mL, 12550 ng/mL, 12600ng/mL, 12650 ng/mL, 12700 ng/mL, 12750 ng/mL, 1200 ng/mL, 121250 ng/mL,12900 ng/mL, 12950 ng/mL, 13000 ng/mL, 13050 ng/mL, 13100 ng/mL, 13150ng/mL, 13200 ng/mL, 13250 ng/mL, 13300 ng/mL, 13350 ng/mL, 13400 ng/mL,13450 ng/mL, 13500 ng/mL, 13550 ng/mL, 13600 ng/mL, 13650 ng/mL, 13700ng/mL, 13750 ng/mL, 1300 ng/mL, 131350 ng/mL, 13900 ng/mL, 13950 ng/mL,14000 ng/mL, 14050 ng/mL, 14100 ng/mL, 14150 ng/mL, 14200 ng/mL, 14250ng/mL, 14300 ng/mL, 14350 ng/mL, 14400 ng/mL, 14450 ng/mL, 14500 ng/mL,14550 ng/mL, 14600 ng/mL, 14650 ng/mL, 14700 ng/mL, 14750 ng/mL, 1400ng/mL, 141450 ng/mL, 14900 ng/mL, 14950 ng/mL, 15000 ng/mL, 15050 ng/mL,15100 ng/mL, 15150 ng/mL, 15200 ng/mL, 15250 ng/mL, 15300 ng/mL, 15350ng/mL, 15400 ng/mL, 15450 ng/mL, 15500 ng/mL, 15550 ng/mL, 15600 ng/mL,15650 ng/mL, 15700 ng/mL, 15750 ng/mL, 1500 ng/mL, 151550 ng/mL, 15900ng/mL, 15950 ng/mL, 16000 ng/mL, 16050 ng/mL, 16100 ng/mL, 16150 ng/mL,16200 ng/mL, 16250 ng/mL, 16300 ng/mL, 16350 ng/mL, 16400 ng/mL, 16450ng/mL, 16500 ng/mL, 16550 ng/mL, 16600 ng/mL, 16650 ng/mL, 16700 ng/mL,16750 ng/mL, 1600 ng/mL, 161650 ng/mL, 16900 ng/mL, 16950 ng/mL, 17000ng/mL, 17050 ng/mL, 17100 ng/mL, 17150 ng/mL, 17200 ng/mL, 17250 ng/mL,17300 ng/mL, 17350 ng/mL, 17400 ng/mL, 17450 ng/mL, 17500 ng/mL, 17550ng/mL, 17600 ng/mL, 17650 ng/mL, 17700 ng/mL, 17750 ng/mL, 1700 ng/mL,171750 ng/mL, 17900 ng/mL, 17950 ng/mL, or 18000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of at least 2000-10000 ng/mL, forexample, a Cmax or mean Cmax that is about (i.e., the specifiednumber±10%) any one of 2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL,2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL,2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL,2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL,3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL,3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL,4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL,4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL,4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL,5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL,5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL,5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL,5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL,6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL,6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL,6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL,7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL,7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL,7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL,8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL,8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL,8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL,8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL,9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL,9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL,9950 ng/mL, 9900 ng/mL, 9950 ng/mL, or 10000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol that is a value that is 80% to 125% of(or bioequivalent to) 800-18000 ng/mL, for example, a Cmax or mean Cmaxthat is a value that is 80% to 125% of (or bioequivalent to) any one of800 ng/mL, 850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100ng/mL, 1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400ng/mL, 1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700ng/mL, 1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 1950 ng/mL, 2000ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL, 4250ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL, 4550ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL, 4850ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL, 5150ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL, 5450ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL, 5750ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL, 6050ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL, 6350ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL, 6650ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL, 6950ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL, 7250ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL, 7550ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL, 7850ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL, 8150ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL, 8450ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL, 8750ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL, 9050ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL, 9350ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL, 9650ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL, 9950ng/mL, 10000 ng/mL, 10050 ng/mL, 10100 ng/mL, 10150 ng/mL, 10200 ng/mL,10250 ng/mL, 10300 ng/mL, 10350 ng/mL, 10400 ng/mL, 10450 ng/mL, 10500ng/mL, 10550 ng/mL, 10600 ng/mL, 10650 ng/mL, 10700 ng/mL, 10750 ng/mL,1000 ng/mL, 101050 ng/mL, 10900 ng/mL, 10950 ng/mL, 11000 ng/mL, 11050ng/mL, 11100 ng/mL, 11150 ng/mL, 11200 ng/mL, 11250 ng/mL, 11300 ng/mL,11350 ng/mL, 11400 ng/mL, 11450 ng/mL, 11500 ng/mL, 11550 ng/mL, 11600ng/mL, 11650 ng/mL, 11700 ng/mL, 11750 ng/mL, 1100 ng/mL, 111150 ng/mL,11900 ng/mL, 11950 ng/mL, 12000 ng/mL, 12050 ng/mL, 12100 ng/mL, 12150ng/mL, 12200 ng/mL, 12250 ng/mL, 12300 ng/mL, 12350 ng/mL, 12400 ng/mL,12450 ng/mL, 12500 ng/mL, 12550 ng/mL, 12600 ng/mL, 12650 ng/mL, 12700ng/mL, 12750 ng/mL, 1200 ng/mL, 121250 ng/mL, 12900 ng/mL, 12950 ng/mL,13000 ng/mL, 13050 ng/mL, 13100 ng/mL, 13150 ng/mL, 13200 ng/mL, 13250ng/mL, 13300 ng/mL, 13350 ng/mL, 13400 ng/mL, 13450 ng/mL, 13500 ng/mL,13550 ng/mL, 13600 ng/mL, 13650 ng/mL, 13700 ng/mL, 13750 ng/mL, 1300ng/mL, 131350 ng/mL, 13900 ng/mL, 13950 ng/mL, 14000 ng/mL, 14050 ng/mL,14100 ng/mL, 14150 ng/mL, 14200 ng/mL, 14250 ng/mL, 14300 ng/mL, 14350ng/mL, 14400 ng/mL, 14450 ng/mL, 14500 ng/mL, 14550 ng/mL, 14600 ng/mL,14650 ng/mL, 14700 ng/mL, 14750 ng/mL, 1400 ng/mL, 141450 ng/mL, 14900ng/mL, 14950 ng/mL, 15000 ng/mL, 15050 ng/mL, 15100 ng/mL, 15150 ng/mL,15200 ng/mL, 15250 ng/mL, 15300 ng/mL, 15350 ng/mL, 15400 ng/mL, 15450ng/mL, 15500 ng/mL, 15550 ng/mL, 15600 ng/mL, 15650 ng/mL, 15700 ng/mL,15750 ng/mL, 1500 ng/mL, 151550 ng/mL, 15900 ng/mL, 15950 ng/mL, 16000ng/mL, 16050 ng/mL, 16100 ng/mL, 16150 ng/mL, 16200 ng/mL, 16250 ng/mL,16300 ng/mL, 16350 ng/mL, 16400 ng/mL, 16450 ng/mL, 16500 ng/mL, 16550ng/mL, 16600 ng/mL, 16650 ng/mL, 16700 ng/mL, 16750 ng/mL, 1600 ng/mL,161650 ng/mL, 16900 ng/mL, 16950 ng/mL, 17000 ng/mL, 17050 ng/mL, 17100ng/mL, 17150 ng/mL, 17200 ng/mL, 17250 ng/mL, 17300 ng/mL, 17350 ng/mL,17400 ng/mL, 17450 ng/mL, 17500 ng/mL, 17550 ng/mL, 17600 ng/mL, 17650ng/mL, 17700 ng/mL, 17750 ng/mL, 1700 ng/mL, 171750 ng/mL, 17900 ng/mL,17950 ng/mL, or 18000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol that is a value that is 80% to 125% of(or bioequivalent to) 2000-10000 ng/mL, for example, a Cmax or mean Cmaxthat is a value that is 80% to 125% of (or bioequivalent to) any one of2000 ng/mL, 2050 ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL,2300 ng/mL, 2350 ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL,2600 ng/mL, 2650 ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL,2900 ng/mL, 2950 ng/mL, 3000 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL,3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL,3950 ng/mL, 4000 ng/mL, 4050 ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL,4250 ng/mL, 4300 ng/mL, 4350 ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL,4550 ng/mL, 4600 ng/mL, 4650 ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL,4850 ng/mL, 4900 ng/mL, 4950 ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL,5150 ng/mL, 5200 ng/mL, 5250 ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL,5450 ng/mL, 5500 ng/mL, 5550 ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL,5750 ng/mL, 5800 ng/mL, 5850 ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL,6050 ng/mL, 6100 ng/mL, 6150 ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL,6350 ng/mL, 6400 ng/mL, 6450 ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL,6650 ng/mL, 6700 ng/mL, 6750 ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL,6950 ng/mL, 7000 ng/mL, 7050 ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL,7250 ng/mL, 7300 ng/mL, 7350 ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL,7550 ng/mL, 7600 ng/mL, 7650 ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL,7850 ng/mL, 7900 ng/mL, 7950 ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL,8150 ng/mL, 8200 ng/mL, 8250 ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL,8450 ng/mL, 8500 ng/mL, 8550 ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL,8750 ng/mL, 800 ng/mL, 8850 ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL,9050 ng/mL, 9100 ng/mL, 9150 ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL,9350 ng/mL, 9400 ng/mL, 9450 ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL,9650 ng/mL, 9700 ng/mL, 9750 ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL,9950 ng/mL, or 10000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 15000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 14000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 13000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 12000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 11000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 10000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 9000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 8000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 7000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 6000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 5000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 4000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 3000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaCmax or mean Cmax of fospropofol of no greater than 2000 ng/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 3200 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 2400 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 1600 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 800 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 600 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 400 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 300 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 200 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 100 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no greater than 50 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 3200 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 2400 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 1600 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 800 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 600 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 400 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 300 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 200 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 100 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol of no less than 50 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 8000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 7000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 6000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 5000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 4500 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 4000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 3000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 2000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no greater than 1000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 8000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 7000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 6000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 5000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 4500 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 4000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 3000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 2000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of fospropofol of no less than 1000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 300 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 200 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 150 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 100 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 50 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 30 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no greater than 20 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no less than 300 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no less than 200 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no less than 150 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no less than 100 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no less than 50 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no less than 30 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of propofol of no less than 20 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 7000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 6000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 5000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 4000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 3500 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 3000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 2000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 1000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 800 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no greater than 700 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 7000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 6000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 5000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 4000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 3500 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 3000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 2000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 1000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 800 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(1hr) or mean AUC_(1hr) of fospropofol of no less than 700 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 800 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 700 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 600 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 500 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 400 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 300 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 200 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no greater than 100 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 800 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 700 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 600 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 500 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 400 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 300 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 200 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of propofol of no less than 100 ng hr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 12000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 8000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 7000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 6000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 5000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 4000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 3000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 2000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no greater than 1000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 12000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 8000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 7000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 6000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 5000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 4000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 3000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 2000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(4hr) or mean AUC_(4hr) of fospropofol of no less than 1000 nghr/mL.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no greaterthan 40-80% of the corresponding AUC_(0-∞) or mean AUC_(0-∞).

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no greaterthan 40% of the corresponding AUC_(0-∞) or mean AUC_(0-∞).

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no greaterthan 50% of the corresponding AUC_(0-∞) or mean AUC_(0-∞).

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no greaterthan 60% of the corresponding AUC_(0-∞) or mean AUC_(0-∞).

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no greaterthan 70% of the corresponding AUC_(0-∞) or mean AUC_(0-∞).

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaAUC_(2hr) or mean AUC_(2hr) of propofol or of fospropofol no greaterthan 80% of the corresponding AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.2.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.29.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.2.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.29.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.2.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.23.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.2.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.23.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(20min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.68.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is less than 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.68.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(60min) ratio on a mean concentration vs. timecurve that is at least 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.55.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is less than 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.55.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(30min)/mean AUC_(120min) ratio on a mean concentration vs. timecurve that is at least 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is less than 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is less than 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is less than 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is less than 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is less than 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is less than 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is less than 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is at least 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is at least 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is at least 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is at least 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is at least 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is at least 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(2hr) ratio on a mean concentration vs. time curvethat is at least 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(1hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is less than 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.9.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.7.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanAUC_(2hr)/mean AUC_(4hr) ratio on a mean concentration vs. time curvethat is at least 0.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio is less than 5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio is less than 4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio is less than 3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio is less than 2.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio that is at least 5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio that is at least 4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio that is at least 3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₆₀ ratio that is at least 2.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio is less than 80.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio is less than 76.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio is less than 70.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio is less than 60.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio is less than 50.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio that is at least 80.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio that is at least 76.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio that is at least 70.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio that is at least 60.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₂₀/mean C₁₂₀ ratio that is at least 50.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio is less than 2.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio is less than 2.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio is less than 2.0.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio is less than 1.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio is less than 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio that is at least 3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio that is at least 2.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio that is at least 2.4.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio that is at least 2.0.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₆₀ ratio that is at least 1.5.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 1.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio is less than 40.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio is less than 36.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio is less than 35.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio is less than 30.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio is less than 25.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio is less than 20.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio is less than 15.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 40.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 36.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 35.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 30.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 25.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 20.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC₃₀/mean C₁₂₀ ratio that is at least 15.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(1hr)/mean C_(2hr) ratio that is less than 3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(1hr)/mean C_(2hr) ratio that is at least 3.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(1hr)/mean C_(4hr) ratio that is less than 8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(1hr)/mean C_(4hr) ratio that is at least 8.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(2hr)/mean C_(4hr) ratio that is less than 6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(2hr)/mean C_(4hr) ratio that is at least 6.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(1hr)/mean C_(2hr) ratio that is less than 11.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma propofol or a plasma fospropofol meanC_(1hr)/mean C_(2hr) ratio that is at least 11.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no greater than 40-80% of the corresponding AUC_(0-∞)or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no greater than 40% of the corresponding AUC_(0-∞) ormean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no greater than 50% of the corresponding AUC_(0-∞) ormean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no greater than 60% of the corresponding AUC_(0-∞) ormean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no greater than 70% of the corresponding AUC_(0-∞) ormean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no greater than 80% of the corresponding AUC_(0-∞) ormean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no less than 40-80% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no less than 40% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no less than 50% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no less than 60% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no less than 70% of AUC_(0-∞) or mean AUC_(0-∞).

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofolor of fospropofol no less than 80% of AUC_(0-∞) or mean AUC_(0-∞).

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1600 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1200 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1000 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-800 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-600 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-400 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-200 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1600 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1200 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1000 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-800 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-600 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-400 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of30-300 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of40-1700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 30-300 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1500 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1300 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1100 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-900 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-500 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1500 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1300 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1100 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-900 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-500 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1500 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1300 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1100 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-900 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-700 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-500 ng/mL for at least 30 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1600 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1200 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1000 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-800 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-600 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-400 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-200 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1600 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1200 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1000 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-800 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-600 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-400 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1500 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1300 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-1100 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-900 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 40-500 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1500 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1300 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-1100 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-900 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 100-500 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1500 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1300 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-1100 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-900 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-700 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration offospropofol of 200-500 ng/mL for at least 60 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1600 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1200 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1000 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-800 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-600 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-400 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-200 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1600 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1200 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1000 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-800 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-600 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-400 ng/mL for at least 90 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1600 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1200 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-1000 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-800 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-600 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-400 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of100-200 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1600 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1200 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-1000 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-800 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-600 ng/mL for at least 120 minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol of200-400 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 30 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 40 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 50 ng/mL for at least 30 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 100 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 150 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 180 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 200 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 300 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 400 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 500 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 600 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 700 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 800 ng/mL for at least 30minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 30 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 40 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 50 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 75 ng/mL for at least 60 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 100 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 150 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 200 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 300 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 400 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 500 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 600 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 700 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 800 ng/mL for at least 60minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 30 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 40 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 50 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 75 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 100 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 150 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 200 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 300 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 400 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 500 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 600 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 700 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol, or of fospropofol, of at least 800 ng/mL for at least 90minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 5 ng/mL for at least 120 minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 15 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 25 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 50 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 100 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 200 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 300 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 400 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 500 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 600 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 700 ng/mL for at least 120minutes.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a plasma concentration or mean concentration ofpropofol or of fospropofol of at least 800 ng/mL for at least 120minutes.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at atime point 0.5-6 hr after the corresponding Tmax or median Tmax that is50-90% of the corresponding plasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol 30minutes after the corresponding Tmax or median Tmax that is 50-90% ofthe corresponding plasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol 30minutes after the corresponding Tmax or median Tmax that is about (i.e.,the specified number±10%) 90% of the corresponding plasma Cmax or meanCmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 30 minutes after the corresponding Tmax or median Tmax thatis about (i.e., the specified number±10%) 80% of the correspondingplasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 30 minutes after the corresponding Tmax or median Tmax thatis about (i.e., the specified number±10%) 70% of the correspondingplasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 30 minutes after the corresponding Tmax or median Tmax thatis about (i.e., the specified number±10%) 60% of the correspondingplasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 30 minutes after the corresponding Tmax or median Tmax thatis about (i.e., the specified number±10%) 50% of the correspondingplasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1 hr after the corresponding Tmax or median Tmax that is50-90% of the corresponding plasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 90% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 80% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 70% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 60% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 50% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1.5 hr after the corresponding Tmax or median Tmax that is50-90% of the corresponding plasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1.5 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 90% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1.5 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 80% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1.5 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 70% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1.5 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 60% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 1.5 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 50% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 2 hr after the corresponding Tmax or median Tmax that is50-90% of the corresponding plasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 2 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 90% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 2 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 80% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 2 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 70% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 2 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 60% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 2 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 50% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 3 hr after the corresponding Tmax or median Tmax that is50-90% of the corresponding plasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 3 hr after the corresponding Tmax or median Tmax that isabout 90% of the corresponding plasma Cmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 3 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 80% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 3 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 70% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 3 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 60% of the corresponding plasmaCmax or mean Cmax.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a plasmaconcentration or mean concentration of propofol or of fospropofol at thetime point 3 hr after the corresponding Tmax or median Tmax that isabout (i.e., the specified number±10%) 50% of the corresponding plasmaCmax or mean Cmax.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a propofol or fospropofol Tmax or median Tmax of0.1 hr-2 hour.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a propofol or fospropofol Tmax or median Tmax of20 min-4 hours.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a propofol or fospropofol Tmax or median Tmax of30 min-4 hours.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a propofol or fospropofol Tmax or median Tmax of60 min-4 hours.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a Tmax or median Tmax for propofol of 0.6 hr-4hours.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a Tmax or median Tmax for propofol of 1 hr-2hours.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a Tmax or median Tmax for fospropofol of 0.1hr-0.7 hours.

In some aspects of the methods of the disclosure, the pharmaceuticalcompositions of the disclosure, when administered to a patient in one ormore doses, results in a Tmax or median Tmax for fospropofol of 0.2hr-0.5 hours.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 20 min.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 30 min.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 45 min.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 1 hr.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 1.5 hr.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 2.0 hr.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 2.5 hr.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 3.0 hr.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 3.5 hr.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, results in a Tmaxor median Tmax for propofol or for fospropofol of about (i.e., thespecified number±10%) 4.0 hr.

In some embodiments, the pharmaceutical compositions of the disclosure,when administered to a patient in one or more doses, produces apulsatile release of forpropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma Cmax for fospropofol has acoefficient of variation that is less than 55%, such as, for example,less than any one of 55%, 54%, 53%, 52%, 51%, 50%, 49%. 48%, 47%, 46%,45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%,31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%,17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma Tmax for fospropofol has acoefficient of variation that is less than 39%, such as, for example,less than any one of 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%,29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%,15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma AUC_(1hr) for fospropofol has acoefficient of variation that is less than 58%, such as, for example,less than any one of 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%,48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%,34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%,20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%,or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma AUC_(2hr) for fospropofol has acoefficient of variation that is less than 57%, such as, for example,less than any one of 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%,47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%,33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%,19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma AUC_(4hr) for fospropofol has acoefficient of variation that is less than 58%, such as, for example,less than any one of 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%,48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%,34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%,20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%,or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma Cmax for propofol has a coefficientof variation that is less than 68%, such as, for example, less than anyone of 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%,55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%,41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%,27%, 26%. 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%. 16%, 15%, 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma Tmax for propofol has a coefficientof variation that is less than 69%, such as, for example, less than anyone of 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%. 58%, 57%,56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%.42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%,28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%. 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma AUC_(1hr) for propofol has acoefficient of variation that is less than 71%, such as, for example,less than any one of 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%,61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%,47%, 46%, 45%. 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%,33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%,19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma AUC_(2hr) for propofol has acoefficient of variation that is less than 65%, such as, for example,less than any one of 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%,55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%,41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%,27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the mean plasma AUC_(4hr) for propofol has acoefficient of variation that is less than 56%, such as, for example,less than any one of 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%,46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%,32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%,18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the plasma fospropofol mean AUC₀₋₉ hrs per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is at least 3.0 ng*h/mL, such as, for example, at least anyone of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2 ng*h/mL/mg, 3.3 ng*h/mL/mg,3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6 ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0 ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4 ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8 ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2 ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6 ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0 ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4 ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8 ng*h/mL/mg, 6.9 ng*h/mL,/mg, 7.0ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2 ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6 ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0 ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4 ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8 ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the plasma fospropofol mean AUC_(0-∞) per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is at least 3.0 ng*h/mL, such as, for example, at least anyone of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2 ng*h/mL/mg, 3.3 ng*h/mL/mg,3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6 ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0 ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4 ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8 ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2 ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6 ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0 ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4 ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8 ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2 ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6 ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0 ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4 ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8 ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the plasma fospropofol mean C_(max) per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is at least 5.0 ng/mL/mg, such as, for example, at leastany one of 5.0 ng/mL/mg, 5.1 ng/mL/mg, 5.2 ng/mL/mg, 5.3 ng/mL/mg, 5.4ng/mL/mg, 5.5 ng/mL/mg, 5.6 ng/mL/mg, 5.7 ng/mL/mg, 5.8 ng/mL/mg, 5.9ng/mL/mg, 6.0 ng/mL/mg, 6.1 ng/mL/mg, 6.2 ng/mL/mg, 6.3 ng/mL/mg, 6.4ng/mL/mg, 6.5 ng/mL/mg, 6.6 ng/mL/mg, 6.7 ng/mL/mg, 6.8 ng/mL/mg, 6.9ng/mL/mg, 7.0 ng/mL/mg, 7.1 ng/mL/mg, 7.2 ng/mL/mg, 7.3 ng/mL/mg, 7.4ng/mL/mg, 7.5 ng/mL/mg, 7.6 ng/mL/mg, 7.7 ng/mL/mg, 7.8 ng/mL/mg, 7.9ng/mL/mg, 8.0 ng/mL/mg, 8.1 ng/mL/mg, 8.2 ng/mL/mg, 8.3 ng/mL/mg, 8.4ng/mL/mg, 8.5 ng/mL/mg, 8.6 ng/mL/mg, 8.7 ng/mL/mg, 8.8 ng/mL/mg, 8.9ng/mL/mg, 9.0 ng/mL/mg, 9.1 ng/mL/mg, 9.2 ng/mL/mg, 9.3 ng/mL/mg, 9.4ng/mL/mg, 9.5 ng/mL/mg, 9.6 ng/mL/mg, 9.7 ng/mL/mg, 9.8 ng/mL/mg, 9.9ng/mL/mg, 10.0 ng/mL/mg, 10.1 ng/mL/mg, 10.2 ng/mL/mg, 10.3 ng/mL/mg,10.4 ng/mL/mg, 10.5 ng/mL/mg, 10.6 ng/mL/mg, 10.7 ng/mL/mg, 10.8ng/mL/mg, 10.9 ng/mL/mg, 11.0 ng/mL/mg, 11.1 ng/mL/mg, 11.2 ng/mL/mg,11.3 ng/mL/mg, 11.4 ng/mL/mg, 11.5 ng/mL/mg, 11.6 ng/mL/mg, 11.7ng/mL/mg, 11.8 ng/mL/mg, 11.9 ng/mL/mg, 12.0 ng/mL/mg, 12.1 ng/mL/mg,12.2 ng/mL/mg, 12.3 ng/mL/mg, 12.4 ng/mL/mg, 12.5 ng/mL/mg, 12.6ng/mL/mg, 12.7 ng/mL/mg, 12.8 ng/mL/mg, 12.9 ng/mL/mg, 13.0 ng/mL/mg,13.1 ng/mL/mg, 13.2 ng/mL/mg, 13.3 ng/mL/mg, 13.4 ng/mL/mg, 13.5ng/mL/mg, 13.6 ng/mL/mg, 13.7 ng/mL/mg, 13.8 ng/mL/mg, 13.9 ng/mL/mg,14.0 ng/mL/mg, 14.1 ng/mL/mg, 14.2 ng/mL/mg, 14.3 ng/mL/mg, 14.4ng/mL/mg, 14.5 ng/mL/mg, 14.6 ng/mL/mg, 14.7 ng/mL/mg, 14.8 ng/mL/mg,14.9 ng/mL/mg, 15.0 ng/mL/mg, 15.1 ng/mL/mg, 15.2 ng/mL/mg, 15.3ng/mL/mg, 15.4 ng/mL/mg, 15.5 ng/mL/mg, 15.6 ng/mL/mg, 15.7 ng/mL/mg,15.8 ng/mL/mg, 15.9 ng/mL/mg, 16.0 ng/mL/mg, 16.1 ng/mL/mg, 16.2ng/mL/mg, 16.3 ng/mL/mg, 16.4 ng/mL/mg, 16.5 ng/mL/mg, 16.6 ng/mL/mg,16.7 ng/mL/mg, 16.8 ng/mL/mg, 16.9 ng/mL/mg, or 17.0 ng/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the plasma propofol mean AUC0-9 hrs per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is at least 0.5 ng*h/mL/mg, such as, for example, at leastany one of 0.5 ng*h/mL/mg, 0.55 ng*h/mL/mg, 0.6 ng*h/mL/mg, 0.65ng*h/mL/mg, 0.7 ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8 ng*h/mL/mg, 0.85ng*h/mL/mg, 0.9 ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0 ng*h/mL/mg, 1.05ng*h/mL/mg, 1.10 ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2 ng*h/mL/mg, 1.25ng*h/mL/mg, 1.3 ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4 ng*h/mL/mg, 1.45ng*h/mL/mg, 1.5 ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6 ng*h/mL/mg, 1.65ng*h/mL/mg, or 1.7 ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the plasma propofol mean AUC_(0-∞) per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is at least 0.5 ng*h/mL/mg, such as, for example, at leastany one of 0.5 ng*h/mL/mg, 0.55 ng*h/mL/mg, 0.6 ng*h/mL/mg, 0.65ng*h/mL/mg, 0.7 ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8 ng*h/mL/mg, 0.85ng*h/mL/mg, 0.9 ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0 ng*h/mL/mg, 1.05ng*h/mL/mg, 1.10 ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2 ng*h/mL/mg, 1.25ng*h/mL/mg, 1.3 ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4 ng*h/mL/mg, 1.45ng*h/mL/mg, 1.5 ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6 ng*h/mL/mg, 1.65ng*h/mL/mg, or 1.7 ng*h/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein the plasma propofol mean C_(max) per mg offospropofol (or a pharmaceutically acceptable salt of fospropofol)administered is at least 0.3 ng/mL/mg, such as, for example, at leastany one of 0.3 ng/mL/mg, 0.35 ng/mL/mg, 0.4 ng/mL/mg, 0.45 ng/mL/mg, 0.5ng/mL/mg, 0.55 ng/mL/mg, 0.6 ng/mL/mg, 0.65 ng/mL/mg, 0.7 ng/mL/mg, 0.75ng/mL/mg, 0.8 ng/mL/mg, 0.85 ng/mL/mg, or 0.9 ng/mL/mg.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hour of the administration at least 1%, atleast 2%, at least 3% at least 4%, at least 5%, at least 6%, at least7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%,at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, atleast 18%, at least 19%, or at least 20% of the patients are headachefree without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 2 hours of the administration at least 5%, atleast 10%, at least 15% at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, or at least 50%, of the patientsare headache free without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 4 hours of the at least 20%, at least 25%, atleast 30%, at least 35% at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, or at least 75%, ofthe patients are headache free without being administered a rescuemedication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 24 hours of the administration at least 50%,at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%,at least 80%, at least 85%, at least 90%, or at least 95%, of thepatients are headache free without being administered a rescuemedication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 48 hours of the administration at least 50%,at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%,at least 80%, at least 85%, at least 90%, or at least 95%, of thepatients are headache free without being administered a rescuemedication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hour of the administration at least 1%, atleast 2%, at least 3% at least 4%, at least 5%, at least 6%, at least7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%,at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, atleast 18%, at least 19%, or at least 20%, of the patients haveexperienced headache pain relief without being administered a rescuemedication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, or atleast 75%, of the patients have experienced headache pain relief withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 2 hours of the administration at least 50%,at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%,at least 80%, at least 85%, at least 90%, or at least 95%, of thepatients have experienced headache pain relief without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 4 hours of the administration at least 50%,at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%,at least 80%, at least 85%, at least 90%, or at least 95%, of thepatients have experienced headache pain relief without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 24 hours of the administration up to at least50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least75%, at least 80%, at least 85%, at least 90%, or at least 95% of thepatients have experienced headache pain relief without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 48 hours of the administration at least 50%,at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%,at least 80%, at least 85%, at least 90%, or at least 95%, of thepatients have experienced headache pain relief without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hour of the administration at least 20%, atleast 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, or atleast 75%, of the patients are free of their most bothersome symptom(MBS) without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 2 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, or at least 80%, of the patients are free of their mostbothersome symptom (MBS) without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 4 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, or at least 80%, of the patients are free of their mostbothersome symptom (MBS) without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 24 hours of the administration up to 80%,such as, for example, up to 80%, up to 75%, up to 70%, up to 65%, up to60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, or up to30%, of the patients are free of their most bothersome symptom (MBS)without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 48 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, or at least 80%, of the patients are free of their mostbothersome symptom (MBS) without being administered a rescue medication.

In some embodiments of these methods, the MBS is nausea, photophobia, orphonophobia.

In some embodiments, the MBS is nausea.

In some embodiments, the MBS is photophobia

In some embodiments, the MBS is phonophobia.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hour of the administration at least 20%, atleast 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, or atleast 75%, of the patients are free of a bothersome symptom withoutbeing administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 2 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, or at least 80%, of the patients are free of a bothersomesymptom without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 4 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, or at least 80%, of the patients are free of a bothersomesymptom without being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 24 hours of the administration up to 80%,such as, for example, up to 80%, up to 75%, up to 70%, up to 65%, up to60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, or up to30%, of the patients are free of a bothersome symptom without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 48 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, or at least 80%, of the patients are free of a bothersomesymptom without being administered a rescue medication.

In some embodiments of these methods, the bothersome symptom is nausea,photophobia, or phonophobia.

In some embodiments, the bothersome symptom is nausea.

In some embodiments, the bothersome symptom is photophobia.

In some embodiments, the bothersome symptom is phonophobia.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had nausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 2 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had nausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 4 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had nausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 24 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had nausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 48 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had nausea at administration are free of their nausea without beingadministered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had photophobia at administration are free of their photophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 2 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had photophobia at administration are free of their photophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 4 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95% of the patientswhom had photophobia at administration are free of their photophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 24 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had photophobia at administration are free of their photophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 48 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had photophobia at administration are free of their photophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 1 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had phonophobia at administration are free of their phonophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 2 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had phonophobia at administration are free of their phonophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 4 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had phonophobia at administration are free of their phonophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 24 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had phonophobia at administration are free of their phonophobiawithout being administered a rescue medication.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure, wherein within 48 hours of the administration at least 20%,at least 25%, at least 30%, at least 35% at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, or at least 95%, of the patientswhom had phonophobia at administration are free of their phonophobiawithout being administered a rescue medication.

In some embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patienta pharmaceutical composition of the disclosure, at 1 hour after theadministration the subject is headache free.

In other embodiments of the methods of treating migraine in a patient inneed thereof, wherein the methods comprise administering to the patienta pharmaceutical composition of the disclosure, at 1 hour after theadministration the subject has experienced headache pain relief.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein the method comprisesadministering to the population a pharmaceutical composition of thedisclosure sooner than 115 minutes after onset of migraine.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein a pharmaceuticalcomposition of the disclosure is administered sooner than 115 minutesafter onset of migraine and the Cmax of propofol is increased comparedto administration after 115 minutes.

In some aspects, the methods are directed to increasing the Cmax ofpropofol and treating migraine in a population of patients in needthereof with fospropofol, a pharmaceutically acceptable salt offospropofol, or mixtures thereof, wherein a pharmaceutical compositionof the disclosure is administered sooner than 115 minutes after onset ofmigraine.

In some aspects, the methods are directed to treating migraine in apopulation of patients in need thereof, wherein a pharmaceuticalcomposition of the disclosure is administered as an acidifiedpharmaceutical dosage form and the Cmax of propofol does not decrease ifthe time to treatment from migraine onset is delayed.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol AUC_(1hr) or thepatient population has a mean AUC_(1hr) of at least 1000 ng*h/mL, suchas, for example, at least 1000 ng*h/mL, at least 1050 ng*h/mL, at least1100 ng*h/mL, at least 1150 ng*h/mL, at least 1200 ng*h/mL, at least1250 ng*h/mL, at least 1300 ng*h/mL, at least 1350 ng*h/mL, at least1400 ng*h/mL, at least 1450 ng*h/mL, at least 1500 ng*h/mL, at least1550 ng*h/mL, at least 1600 ng*h/mL, at least 1650 ng*h/mL, at least1700 ng*h/mL, at least 1750 ng*h/mL, at least 1800 ng*h/mL, at least1850 ng*h/mL, at least 1900 ng*h/mL, at least 1950 ng*h/mL, at least2000 ng*h/mL, at least 2050 ng*h/mL, at least 2100 ng*h/mL, at least2150 ng*h/mL, at least 2200 ng*h/mL, at least 2250 ng*h/mL, at least2300 ng*h/mL, at least 2350 ng*h/mL, at least 2400 ng*h/mL, at least2450 ng*h/mL, at least 2500 ng*h/mL, at least 2550 ng*h/mL, at least2600 ng*h/mL, at least 2650 ng*h/mL, at least 2700 ng*h/mL, at least2750 ng*h/mL, at least 2800 ng*h/mL, at least 2850 ng*h/mL, at least2900 ng*h/mL, at least 2950 ng*h/mL, at least 3000 ng*h/mL, at least3050 ng*h/mL, at least 3100 ng*h/mL, at least 3150 ng*h/mL, at least3200 ng*h/mL, at least 3250 ng*h/mL, at least 3300 ng*h/mL, at least3350 ng*h/mL, at least 3400 ng*h/mL, at least 3450 ng*h/mL, at least3500 ng*h/mL, at least 3550 ng*h/mL, at least 3600 ng*h/mL, at least3650 ng*h/mL, at least 3700 ng*h/mL, at least 3750 ng*h/mL, at least3800 ng*h/mL, at least 3850 ng*h/mL, at least 3900 ng*h/mL, at least3950 ng*h/mL, at least 4000 ng*h/mL, at least 4050 ng*h/mL, at least4100 ng*h/mL, at least 4150 ng*h/mL, at least 4200 ng*h/mL, at least4250 ng*h/mL, at least 4300 ng*h/mL, at least 4350 ng*h/mL, at least4400 ng*h/mL, at least 4450 ng*h/mL, at least 4500 ng*h/mL, at least4550 ng*h/mL, at least 4600 ng*h/mL, at least 4650 ng*h/mL, at least4700 ng*h/mL, at least 4750 ng*h/mL, at least 4800 ng*h/mL, at least4850 ng*h/mL, at least 4900 ng*h/mL, at least 4950 ng*h/mL, at least5000 ng*h/mL, at least 5050 ng*h/mL, at least 5100 ng*h/mL, at least5150 ng*h/mL, at least 5200 ng*h/mL, at least 5250 ng*h/mL, at least5300 ng*h/mL, at least 5350 ng*h/mL, at least 5400 ng*h/mL, at least5450 ng*h/mL, at least 5500 ng*h/mL, at least 5550 ng*h/mL, at least5600 ng*h/mL, at least 5650 ng*h/mL, at least 5700 ng*h/mL, at least5750 ng*h/mL, at least 5800 ng*h/mL, at least 5850 ng*h/mL, at least5900 ng*h/mL, at least 5950 ng*h/mL, at least 6000 ng*h/mL, at least6050 ng*h/mL, at least 6100 ng*h/mL, at least 6150 ng*h/mL, at least6200 ng*h/mL, at least 6250 ng*h/mL, at least 6300 ng*h/mL, at least6350 ng*h/mL, at least 6400 ng*h/mL, at least 6450 ng*h/mL, at least6500 ng*h/mL, at least 6550 ng*h/mL, at least 6600 ng*h/mL, at least6650 ng*h/mL, at least 6700 ng*h/mL, at least 6750 ng*h/mL, at least6800 ng*h/mL, at least 6850 ng*h/mL, at least 6900 ng*h/mL, at least6950 ng*h/mL, at least 7000 ng*h/mL, at least 7050 ng*h/mL, at least7100 ng*h/mL, at least 7150 ng*h/mL, at least 7200 ng*h/mL, at least7250 ng*h/mL, at least 7300 ng*h/mL, at least 7350 ng*h/mL, at least7400 ng*h/mL, at least 7450 ng*h/mL, at least 7500 ng*h/mL, at least7550 ng*h/mL, at least 7600 ng*h/mL, at least 7650 ng*h/mL, at least7700 ng*h/mL, at least 7750 ng*h/mL, at least 7800 ng*h/mL, at least7850 ng*h/mL, at least 7900 ng*h/mL, at least 7950 ng*h/mL, at least8000 ng*h/mL, at least 8050 ng*h/mL, at least 8100 ng*h/mL, at least8150 ng*h/mL, at least 8200 ng*h/mL, at least 8250 ng*h/mL, at least8300 ng*h/mL, at least 8350 ng*h/mL, at least 8400 ng*h/mL, at least8450 ng*h/mL, at least 8500 ng*h/mL, at least 8550 ng*h/mL, at least8600 ng*h/mL, at least 8650 ng*h/mL, at least 8700 ng*h/mL, at least8750 ng*h/mL, at least 8800 ng*h/mL, at least 8850 ng*h/mL, at least8900 ng*h/mL, at least 8950 ng*h/mL, at least 9000 ng*h/mL, at least9050 ng*h/mL, at least 9100 ng*h/mL, at least 9150 ng*h/mL, at least9200 ng*h/mL, at least 9250 ng*h/mL, at least 9300 ng*h/mL, at least9350 ng*h/mL, at least 9400 ng*h/mL, at least 9450 ng*h/mL, at least9500 ng*h/mL, at least 9550 ng*h/mL, at least 9600 ng*h/mL, at least9650 ng*h/mL, at least 9700 ng*h/mL, at least 9750 ng*h/mL, at least9800 ng*h/mL, at least 9850 ng*h/mL, at least 9900 ng*h/mL, at least9950 ng*h/mL, or at least 10000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol AUC_(1hr) or thepatient population has a mean AUC_(1hr) as set forth herein and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol AUC_(1hr) or thepatient population has a mean AUC_(1hr) of at least 6000 ng*h/mL and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol AUC_(1hr) or thepatient population has a mean AUC_(1hr) as set forth herein and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol AUC_(1hr) or thepatient population has a mean AUC_(1hr) of at least 2000 ng*h/mL and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol AUC_(1hr) or thepatient population has a mean AUC_(1hr) as set forth herein and thepatient is no longer experiencing its most bothersome symptom. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol AUC_(1hr) or thepatient population has a mean AUC_(1hr) of at least 3000 ng*h/mL and thepatient is no longer experiencing its most bothersome symptom (MBS). Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has a plasma fospropofol concentration(C_(1hr)) or the patient population has a mean C_(1hr) of at least 500ng/mL, such as, for example, at least 500 ng/mL, at least 550 ng/mL, atleast 600 ng/mL, at least 650 ng/mL, at least 700 ng/mL, at least 750ng/mL, at least 800 ng/mL, at least 850 ng/mL, at least 900 ng/mL, atleast 950 ng/mL, 1000 ng/mL, such as, for example, at least 1000 ng/mL,at least 1050 ng/mL, at least 1100 ng/mL, at least 1150 ng/mL, at least1200 ng/mL, at least 1250 ng/mL, at least 1300 ng/mL, at least 1350ng/mL, at least 1400 ng/mL, at least 1450 ng/mL, at least 1500 ng/mL, atleast 1550 ng/mL, at least 1600 ng/mL, at least 1650 ng/mL, at least1700 ng/mL, at least 1750 ng/mL, at least 1800 ng/mL, at least 1850ng/mL, at least 1900 ng/mL, at least 1950 ng/mL, at least 2000 ng/mL, atleast 2050 ng/mL, at least 2100 ng/mL, at least 2150 ng/mL, at least2200 ng/mL, at least 2250 ng/mL, at least 2300 ng/mL, at least 2350ng/mL, at least 2400 ng/mL, at least 2450 ng/mL, at least 2500 ng/mL, atleast 2550 ng/mL, at least 2600 ng/mL, at least 2650 ng/mL, at least2700 ng/mL, at least 2750 ng/mL, at least 2800 ng/mL, at least 2850ng/mL, at least 2900 ng/mL, at least 2950 ng/mL, at least 3000 ng/mL, atleast 3050 ng/mL, at least 3100 ng/mL, at least 3150 ng/mL, at least3200 ng/mL, at least 3250 ng/mL, at least 3300 ng/mL, at least 3350ng/mL, at least 3400 ng/mL, at least 3450 ng/mL, at least 3500 ng/mL, atleast 3550 ng/mL, at least 3600 ng/mL, at least 3650 ng/mL, at least3700 ng/mL, at least 3750 ng/mL, at least 3800 ng/mL, at least 3850ng/mL, at least 3900 ng/mL, at least 3950 ng/mL, at least 4000 ng/mL, atleast 4050 ng/mL, at least 4100 ng/mL, at least 4150 ng/mL, at least4200 ng/mL, at least 4250 ng/mL, at least 4300 ng/mL, at least 4350ng/mL, at least 4400 ng/mL, at least 4450 ng/mL, at least 4500 ng/mL, atleast 4550 ng/mL, at least 4600 ng/mL, at least 4650 ng/mL, at least4700 ng/mL, at least 4750 ng/mL, at least 4800 ng/mL, at least 4850ng/mL, at least 4900 ng/mL, at least 4950 ng/mL, or at least 5000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has a plasma fospropofol concentration(C_(1hr)) or the patient population has a mean C_(1hr) as set forthherein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol concentration(C_(1hr)) or the patient population has a mean C_(1hr) of at least 2000ng/mL and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol concentration(C_(1hr)) or the patient population has a mean C_(1hr) as set forthherein and the patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol concentration(C_(1hr)) or the patient population has a mean C_(1hr) of at least 1000ng/mL and the patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol concentration(C_(1hr)) or the patient population has a mean C_(1hr) as set forthherein and the patient is no longer experiencing its most bothersomesymptom. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea. In someembodiments, the MBS is photophobia. In some embodiments, the MBS isphonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma fospropofol concentration(C_(1hr)) or the patient population has a mean C_(1hr) of at least 1000ng/mL and the patient is no longer experiencing its most bothersomesymptom (MBS). In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea. In someembodiments, the MBS is photophobia. In some embodiments, the MBS isphonophobia.

Fospro—2 Hours

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol AUC_(2hr) or thepatient population has a mean AUC_(2hr) of at least 1000 ng*h/mL, suchas, for example, at least 1000 ng*h/mL, at least 1050 ng*h/mL, at least1100 ng*h/mL, at least 1150 ng*h/mL, at least 1200 ng*h/mL, at least1250 ng*h/mL, at least 1300 ng*h/mL, at least 1350 ng*h/mL, at least1400 ng*h/mL, at least 1450 ng*h/mL, at least 1500 ng*h/mL, at least1550 ng*h/mL, at least 1600 ng*h/mL, at least 1650 ng*h/mL, at least1700 ng*h/mL, at least 1750 ng*h/mL, at least 1800 ng*h/mL, at least1850 ng*h/mL, at least 1900 ng*h/mL, at least 1950 ng*h/mL, at least2000 ng*h/mL, at least 2050 ng*h/mL, at least 2100 ng*h/mL, at least2150 ng*h/mL, at least 2200 ng*h/mL, at least 2250 ng*h/mL, at least2300 ng*h/mL, at least 2350 ng*h/mL, at least 2400 ng*h/mL, at least2450 ng*h/mL, at least 2500 ng*h/mL, at least 2550 ng*h/mL, at least2600 ng*h/mL, at least 2650 ng*h/mL, at least 2700 ng*h/mL, at least2750 ng*h/mL, at least 2800 ng*h/mL, at least 2850 ng*h/mL, at least2900 ng*h/mL, at least 2950 ng*h/mL, at least 3000 ng*h/mL, at least3050 ng*h/mL, at least 3100 ng*h/mL, at least 3150 ng*h/mL, at least3200 ng*h/mL, at least 3250 ng*h/mL, at least 3300 ng*h/mL, at least3350 ng*h/mL, at least 3400 ng*h/mL, at least 3450 ng*h/mL, at least3500 ng*h/mL, at least 3550 ng*h/mL, at least 3600 ng*h/mL, at least3650 ng*h/mL, at least 3700 ng*h/mL, at least 3750 ng*h/mL, at least3800 ng*h/mL, at least 3850 ng*h/mL, at least 3900 ng*h/mL, at least3950 ng*h/mL, at least 4000 ng*h/mL, at least 4050 ng*h/mL, at least4100 ng*h/mL, at least 4150 ng*h/mL, at least 4200 ng*h/mL, at least4250 ng*h/mL, at least 4300 ng*h/mL, at least 4350 ng*h/mL, at least4400 ng*h/mL, at least 4450 ng*h/mL, at least 4500 ng*h/mL, at least4550 ng*h/mL, at least 4600 ng*h/mL, at least 4650 ng*h/mL, at least4700 ng*h/mL, at least 4750 ng*h/mL, at least 4800 ng*h/mL, at least4850 ng*h/mL, at least 4900 ng*h/mL, at least 4950 ng*h/mL, at least5000 ng*h/mL, at least 5050 ng*h/mL, at least 5100 ng*h/mL, at least5150 ng*h/mL, at least 5200 ng*h/mL, at least 5250 ng*h/mL, at least5300 ng*h/mL, at least 5350 ng*h/mL, at least 5400 ng*h/mL, at least5450 ng*h/mL, at least 5500 ng*h/mL, at least 5550 ng*h/mL, at least5600 ng*h/mL, at least 5650 ng*h/mL, at least 5700 ng*h/mL, at least5750 ng*h/mL, at least 5800 ng*h/mL, at least 5850 ng*h/mL, at least5900 ng*h/mL, at least 5950 ng*h/mL, at least 6000 ng*h/mL, at least6050 ng*h/mL, at least 6100 ng*h/mL, at least 6150 ng*h/mL, at least6200 ng*h/mL, at least 6250 ng*h/mL, at least 6300 ng*h/mL, at least6350 ng*h/mL, at least 6400 ng*h/mL, at least 6450 ng*h/mL, at least6500 ng*h/mL, at least 6550 ng*h/mL, at least 6600 ng*h/mL, at least6650 ng*h/mL, at least 6700 ng*h/mL, at least 6750 ng*h/mL, at least6800 ng*h/mL, at least 6850 ng*h/mL, at least 6900 ng*h/mL, at least6950 ng*h/mL, at least 7000 ng*h/mL, at least 7050 ng*h/mL, at least7100 ng*h/mL, at least 7150 ng*h/mL, at least 7200 ng*h/mL, at least7250 ng*h/mL, at least 7300 ng*h/mL, at least 7350 ng*h/mL, at least7400 ng*h/mL, at least 7450 ng*h/mL, at least 7500 ng*h/mL, at least7550 ng*h/mL, at least 7600 ng*h/mL, at least 7650 ng*h/mL, at least7700 ng*h/mL, at least 7750 ng*h/mL, at least 7800 ng*h/mL, at least7850 ng*h/mL, at least 7900 ng*h/mL, at least 7950 ng*h/mL, at least8000 ng*h/mL, at least 8050 ng*h/mL, at least 8100 ng*h/mL, at least8150 ng*h/mL, at least 8200 ng*h/mL, at least 8250 ng*h/mL, at least8300 ng*h/mL, at least 8350 ng*h/mL, at least 8400 ng*h/mL, at least8450 ng*h/mL, at least 8500 ng*h/mL, at least 8550 ng*h/mL, at least8600 ng*h/mL, at least 8650 ng*h/mL, at least 8700 ng*h/mL, at least8750 ng*h/mL, at least 8800 ng*h/mL, at least 8850 ng*h/mL, at least8900 ng*h/mL, at least 8950 ng*h/mL, at least 9000 ng*h/mL, at least9050 ng*h/mL, at least 9100 ng*h/mL, at least 9150 ng*h/mL, at least9200 ng*h/mL, at least 9250 ng*h/mL, at least 9300 ng*h/mL, at least9350 ng*h/mL, at least 9400 ng*h/mL, at least 9450 ng*h/mL, at least9500 ng*h/mL, at least 9550 ng*h/mL, at least 9600 ng*h/mL, at least9650 ng*h/mL, at least 9700 ng*h/mL, at least 9750 ng*h/mL, at least9800 ng*h/mL, at least 9850 ng*h/mL, at least 9900 ng*h/mL, at least9950 ng*h/mL, or at least 10000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol AUC_(2hr) or thepatient population has a mean AUC_(2hr) as set forth herein and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol AUC_(2hr) or thepatient population has a mean AUC_(2hr) of at least 3000 ng*h/mL and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol AUC_(2hr) or thepatient population has a mean AUC_(2hr) as set forth herein and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol AUC_(2hr) or thepatient population has a mean AUC_(2hr) of at least 1000 ng*h/mL and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol AUC_(2hr) or thepatient population has a mean AUC_(2hr) as set forth herein and thepatient is no longer experiencing its most bothersome symptom. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol AUC_(2hr) or thepatient population has a mean AUC_(2hr) of at least 1000 ng*h/mL and thepatient is no longer experiencing its most bothersome symptom (MBS). Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hour after theadministration the patient has plasma fospropofol concentration(C_(2hr)) or the patient population has a mean C_(2hr) of at least 25ng/mL, such as, for example, at least 25 ng/mL, at least 50 ng/mL, atleast 75 ng/mL, at least 100 ng/mL, at least 125 ng/mL, at least 150ng/mL, at least 175 ng/mL, at least 200 ng/mL, at least 225 ng/mL, atleast 250 ng/mL, 275 ng/mL, at least 300 ng/mL, at least 325 ng/mL, atleast 350 ng/mL, at least 400 ng/mL, at least 425 ng/mL, at least 450ng/mL, at least 475 ng/mL, at least 500 ng/mL, at least 525 ng/mL, atleast 550 ng/mL, at least 575 ng/mL, at least 600 ng/mL, at least 625ng/mL, at least 650 ng/mL, at least 675 ng/mL, at least 700 ng/mL, atleast 725 ng/mL, at least 750 ng/mL, at least 775 ng/mL, at least 800ng/mL, at least 825 ng/mL, at least 850 ng/mL, at least 875 ng/mL, atleast 900 ng/mL, at least 925 ng/mL, at least 950 ng/mL, at least 975ng/mL, at least 1000 ng/mL, at least 1100 ng/mL, at least 1125 ng/mL, atleast 1150 ng/mL, at least 1175 ng/mL, at least 1200 ng/mL, at least1225 ng/mL, at least 1250 ng/mL, 1275 ng/mL, at least 1300 ng/mL, atleast 1325 ng/mL, at least 1350 ng/mL, at least 1400 ng/mL, at least1425 ng/mL, at least 1450 ng/mL, at least 1475 ng/mL, at least 1500ng/mL, at least 1525 ng/mL, at least 1550 ng/mL, at least 1575 ng/mL, atleast 1600 ng/mL, at least 1625 ng/mL, at least 1650 ng/mL, at least1675 ng/mL, at least 1700 ng/mL, at least 1725 ng/mL, at least 1750ng/mL, at least 1775 ng/mL, at least 1800 ng/mL, at least 1825 ng/mL, atleast 1850 ng/mL, at least 1875 ng/mL, at least 1900 ng/mL, at least1925 ng/mL, at least 1950 ng/mL, at least 1975 ng/mL, or at least 2000ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has a plasma fospropofol concentration(C_(2hr)) or the patient population has a mean C_(2hr) as set forthherein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hour after theadministration the patient has plasma fospropofol concentration(C_(2hr)) or the patient population has a mean C_(2hr) of at least 100ng/mL and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol concentration(C_(2hr)) or the patient population has a mean C_(2hr) as set forthherein and the patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol concentration(C_(2hr)) or the patient population has a mean C_(2hr) of at least 40ng/mL and the patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol concentration(C_(2hr)) or the patient population has a mean C_(2hr) as set forthherein and the patient is no longer experiencing its most bothersomesymptom. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea. In someembodiments, the MBS is photophobia. In some embodiments, the MBS isphonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma fospropofol concentration(C_(2hr)) or the patient population has a mean C_(2hr) of at least 50ng/mL and the patient is no longer experiencing its most bothersomesymptom (MBS). In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea. In someembodiments, the MBS is photophobia. In some embodiments, the MBS isphonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom, and the plasma Cmaxor the patient population mean Cmax of propofol is at least any one of200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL,850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL,1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL,1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL,1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 2000 ng/mL, 2050 ng/mL,2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL,2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL,2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL,3000 ng/mL, 3050 ng/mL, 3100 ng/mL, 3150 ng/mL, 3200 ng/mL, 3250 ng/mL,3300 ng/mL, 3350 ng/mL, 3400 ng/mL, 3450 ng/mL, 3500 ng/mL, 3550 ng/mL,3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL,3900 ng/mL, 3950 ng/mL, or 4000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the plasma Cmax orthe patient population mean Cmax of fospropofol (or a pharmaceuticallyacceptable salt of fospropofol) is at least any one of 800 ng/mL, 850ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 1950 ng/mL, 2000 ng/mL, 2050ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950ng/mL, 3000 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000ng/mL, 4050 ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300ng/mL, 4350 ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600ng/mL, 4650 ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900ng/mL, 4950 ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200ng/mL, 5250 ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500ng/mL, 5550 ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800ng/mL, 5850 ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100ng/mL, 6150 ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400ng/mL, 6450 ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700ng/mL, 6750 ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000ng/mL, 7050 ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300ng/mL, 7350 ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600ng/mL, 7650 ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900ng/mL, 7950 ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200ng/mL, 8250 ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500ng/mL, 8550 ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800ng/mL, 8850 ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100ng/mL, 9150 ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400ng/mL, 9450 ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700ng/mL, 9750 ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL, 9950 ng/mL, 10000ng/mL, 10050 ng/mL, 10100 ng/mL, 10150 ng/mL, 10200 ng/mL, 10250 ng/mL,10300 ng/mL, 10350 ng/mL, 10400 ng/mL, 10450 ng/mL, 10500 ng/mL, 10550ng/mL, 10600 ng/mL, 10650 ng/mL, 10700 ng/mL, 10750 ng/mL, 1000 ng/mL,101050 ng/mL, 10900 ng/mL, 10950 ng/mL, 11000 ng/mL, 11050 ng/mL, 11100ng/mL, 11150 ng/mL, 11200 ng/mL, 11250 ng/mL, 11300 ng/mL, 11350 ng/mL,11400 ng/mL, 11450 ng/mL, 11500 ng/mL, 11550 ng/mL, 11600 ng/mL, 11650ng/mL, 11700 ng/mL, 11750 ng/mL, 1100 ng/mL, 111150 ng/mL, 11900 ng/mL,11950 ng/mL, 12000 ng/mL, 12050 ng/mL, 12100 ng/mL, 12150 ng/mL, 12200ng/mL, 12250 ng/mL, 12300 ng/mL, 12350 ng/mL, 12400 ng/mL, 12450 ng/mL,12500 ng/mL, 12550 ng/mL, 12600 ng/mL, 12650 ng/mL, 12700 ng/mL, 12750ng/mL, 1200 ng/mL, 121250 ng/mL, 12900 ng/mL, 12950 ng/mL, 13000 ng/mL,13050 ng/mL, 13100 ng/mL, 13150 ng/mL, 13200 ng/mL, 13250 ng/mL, 13300ng/mL, 13350 ng/mL, 13400 ng/mL, 13450 ng/mL, 13500 ng/mL, 13550 ng/mL,13600 ng/mL, 13650 ng/mL, 13700 ng/mL, 13750 ng/mL, 1300 ng/mL, 131350ng/mL, 13900 ng/mL, 13950 ng/mL, 14000 ng/mL, 14050 ng/mL, 14100 ng/mL,14150 ng/mL, 14200 ng/mL, 14250 ng/mL, 14300 ng/mL, 14350 ng/mL, 14400ng/mL, 14450 ng/mL, 14500 ng/mL, 14550 ng/mL, 14600 ng/mL, 14650 ng/mL,14700 ng/mL, 14750 ng/mL, 1400 ng/mL, 141450 ng/mL, 14900 ng/mL, 14950ng/mL, 15000 ng/mL, 15050 ng/mL, 15100 ng/mL, 15150 ng/mL, 15200 ng/mL,15250 ng/mL, 15300 ng/mL, 15350 ng/mL, 15400 ng/mL, 15450 ng/mL, 15500ng/mL, 15550 ng/mL, 15600 ng/mL, 15650 ng/mL, 15700 ng/mL, 15750 ng/mL,1500 ng/mL, 151550 ng/mL, 15900 ng/mL, 15950 ng/mL, 16000 ng/mL, 16050ng/mL, 16100 ng/mL, 16150 ng/mL, 16200 ng/mL, 16250 ng/mL, 16300 ng/mL,16350 ng/mL, 16400 ng/mL, 16450 ng/mL, 16500 ng/mL, 16550 ng/mL, 16600ng/mL, 16650 ng/mL, 16700 ng/mL, 16750 ng/mL, 1600 ng/mL, 161650 ng/mL,16900 ng/mL, 16950 ng/mL, 17000 ng/mL, 17050 ng/mL, 17100 ng/mL, 17150ng/mL, 17200 ng/mL, 17250 ng/mL, 17300 ng/mL, 17350 ng/mL, 17400 ng/mL,17450 ng/mL, 17500 ng/mL, 17550 ng/mL, 17600 ng/mL, 17650 ng/mL, 17700ng/mL, 17750 ng/mL, 1700 ng/mL, 171750 ng/mL, 17900 ng/mL, 17950 ng/mL,or 18000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the propofolplasma AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered or the propofol patient populationmean AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered is, at least any one of 0.5ng*h/mL/mg, 0.55 ng*h/mL/mg, 0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8 ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0 ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2 ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4 ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6 ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the fospropofolplasma AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered or the fospropofol patient populationmean AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered is at least 3.0 ng*h/mL, such as, forexample, at least any one of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8 ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2 ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6 ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0 ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4 ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8 ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2 ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6 ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0 ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4 ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8 ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2 ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6 ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom, and the plasma Cmaxor the patient population mean Cmax of propofol is at least any one of200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL,850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL,1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL,1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL,1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 2000 ng/mL, 2050 ng/mL,2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL,2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL,2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL,3000 ng/mL, 3050 ng/mL, 3100 ng/mL, 3150 ng/mL, 3200 ng/mL, 3250 ng/mL,3300 ng/mL, 3350 ng/mL, 3400 ng/mL, 3450 ng/mL, 3500 ng/mL, 3550 ng/mL,3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL,3900 ng/mL, 3950 ng/mL, or 4000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the plasma Cmax orthe patient population mean Cmax of fospropofol (or a pharmaceuticallyacceptable salt of fospropofol) is at least any one of 800 ng/mL, 850ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 1950 ng/mL, 2000 ng/mL, 2050ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950ng/mL, 3000 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000ng/mL, 4050 ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300ng/mL, 4350 ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600ng/mL, 4650 ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900ng/mL, 4950 ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200ng/mL, 5250 ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500ng/mL, 5550 ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800ng/mL, 5850 ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100ng/mL, 6150 ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400ng/mL, 6450 ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700ng/mL, 6750 ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000ng/mL, 7050 ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300ng/mL, 7350 ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600ng/mL, 7650 ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900ng/mL, 7950 ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200ng/mL, 8250 ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500ng/mL, 8550 ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800ng/mL, 8850 ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100ng/mL, 9150 ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400ng/mL, 9450 ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700ng/mL, 9750 ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL, 9950 ng/mL, 10000ng/mL, 10050 ng/mL, 10100 ng/mL, 10150 ng/mL, 10200 ng/mL, 10250 ng/mL,10300 ng/mL, 10350 ng/mL, 10400 ng/mL, 10450 ng/mL, 10500 ng/mL, 10550ng/mL, 10600 ng/mL, 10650 ng/mL, 10700 ng/mL, 10750 ng/mL, 1000 ng/mL,101050 ng/mL, 10900 ng/mL, 10950 ng/mL, 11000 ng/mL, 11050 ng/mL, 11100ng/mL, 11150 ng/mL, 11200 ng/mL, 11250 ng/mL, 11300 ng/mL, 11350 ng/mL,11400 ng/mL, 11450 ng/mL, 11500 ng/mL, 11550 ng/mL, 11600 ng/mL, 11650ng/mL, 11700 ng/mL, 11750 ng/mL, 1100 ng/mL, 111150 ng/mL, 11900 ng/mL,11950 ng/mL, 12000 ng/mL, 12050 ng/mL, 12100 ng/mL, 12150 ng/mL, 12200ng/mL, 12250 ng/mL, 12300 ng/mL, 12350 ng/mL, 12400 ng/mL, 12450 ng/mL,12500 ng/mL, 12550 ng/mL, 12600 ng/mL, 12650 ng/mL, 12700 ng/mL, 12750ng/mL, 1200 ng/mL, 121250 ng/mL, 12900 ng/mL, 12950 ng/mL, 13000 ng/mL,13050 ng/mL, 13100 ng/mL, 13150 ng/mL, 13200 ng/mL, 13250 ng/mL, 13300ng/mL, 13350 ng/mL, 13400 ng/mL, 13450 ng/mL, 13500 ng/mL, 13550 ng/mL,13600 ng/mL, 13650 ng/mL, 13700 ng/mL, 13750 ng/mL, 1300 ng/mL, 131350ng/mL, 13900 ng/mL, 13950 ng/mL, 14000 ng/mL, 14050 ng/mL, 14100 ng/mL,14150 ng/mL, 14200 ng/mL, 14250 ng/mL, 14300 ng/mL, 14350 ng/mL, 14400ng/mL, 14450 ng/mL, 14500 ng/mL, 14550 ng/mL, 14600 ng/mL, 14650 ng/mL,14700 ng/mL, 14750 ng/mL, 1400 ng/mL, 141450 ng/mL, 14900 ng/mL, 14950ng/mL, 15000 ng/mL, 15050 ng/mL, 15100 ng/mL, 15150 ng/mL, 15200 ng/mL,15250 ng/mL, 15300 ng/mL, 15350 ng/mL, 15400 ng/mL, 15450 ng/mL, 15500ng/mL, 15550 ng/mL, 15600 ng/mL, 15650 ng/mL, 15700 ng/mL, 15750 ng/mL,1500 ng/mL, 151550 ng/mL, 15900 ng/mL, 15950 ng/mL, 16000 ng/mL, 16050ng/mL, 16100 ng/mL, 16150 ng/mL, 16200 ng/mL, 16250 ng/mL, 16300 ng/mL,16350 ng/mL, 16400 ng/mL, 16450 ng/mL, 16500 ng/mL, 16550 ng/mL, 16600ng/mL, 16650 ng/mL, 16700 ng/mL, 16750 ng/mL, 1600 ng/mL, 161650 ng/mL,16900 ng/mL, 16950 ng/mL, 17000 ng/mL, 17050 ng/mL, 17100 ng/mL, 17150ng/mL, 17200 ng/mL, 17250 ng/mL, 17300 ng/mL, 17350 ng/mL, 17400 ng/mL,17450 ng/mL, 17500 ng/mL, 17550 ng/mL, 17600 ng/mL, 17650 ng/mL, 17700ng/mL, 17750 ng/mL, 1700 ng/mL, 171750 ng/mL, 17900 ng/mL, 17950 ng/mL,or 18000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the propofolplasma AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered or the propofol patient populationmean AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered is, at least any one of 0.5ng*h/mL/mg, 0.55 ng*h/mL/mg, 0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8 ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0 ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2 ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4 ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6 ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the fospropofolplasma AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered or the fospropofol patient populationmean AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered is at least 3.0 ng*h/mL, such as, forexample, at least any one of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8 ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2 ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6 ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0 ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4 ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8 ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2 ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6 ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0 ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4 ng*h/mL/mg, 7.5 ng*h/mL/mg, 7.6ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8 ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2 ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6 ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom, and the plasma Cmaxor the patient population mean Cmax of propofol is at least any one of200 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500ng/mL, 550 ng/mL, 600 ng/mL, 650 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL,850 ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL,1150 ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL,1450 ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL,1750 ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 2000 ng/mL, 2050 ng/mL,2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350 ng/mL,2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650 ng/mL,2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950 ng/mL,3000 ng/mL, 3050 ng/mL, 3100 ng/mL, 3150 ng/mL, 3200 ng/mL, 3250 ng/mL,3300 ng/mL, 3350 ng/mL, 3400 ng/mL, 3450 ng/mL, 3500 ng/mL, 3550 ng/mL,3600 ng/mL, 3650 ng/mL, 3700 ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL,3900 ng/mL, 3950 ng/mL, or 4000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the plasma Cmax orthe patient population mean Cmax of fospropofol (or a pharmaceuticallyacceptable salt of fospropofol) is at least any one of 800 ng/mL, 850ng/mL, 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1050 ng/mL, 1100 ng/mL, 1150ng/mL, 1200 ng/mL, 1250 ng/mL, 1300 ng/mL, 1350 ng/mL, 1400 ng/mL, 1450ng/mL, 1500 ng/mL, 1550 ng/mL, 1600 ng/mL, 1650 ng/mL, 1700 ng/mL, 1750ng/mL, 1800 ng/mL, 1850 ng/mL, 1900 ng/mL, 1950 ng/mL, 2000 ng/mL, 2050ng/mL, 2100 ng/mL, 2150 ng/mL, 2200 ng/mL, 2250 ng/mL, 2300 ng/mL, 2350ng/mL, 2400 ng/mL, 2450 ng/mL, 2500 ng/mL, 2550 ng/mL, 2600 ng/mL, 2650ng/mL, 2700 ng/mL, 2750 ng/mL, 2800 ng/mL, 2850 ng/mL, 2900 ng/mL, 2950ng/mL, 3000 ng/mL, 3500 ng/mL, 3550 ng/mL, 3600 ng/mL, 3650 ng/mL, 3700ng/mL, 3750 ng/mL, 3800 ng/mL, 3850 ng/mL, 3900 ng/mL, 3950 ng/mL, 4000ng/mL, 4050 ng/mL, 4100 ng/mL, 4150 ng/mL, 4200 ng/mL, 4250 ng/mL, 4300ng/mL, 4350 ng/mL, 4400 ng/mL, 4450 ng/mL, 4500 ng/mL, 4550 ng/mL, 4600ng/mL, 4650 ng/mL, 4700 ng/mL, 4750 ng/mL, 4800 ng/mL, 4850 ng/mL, 4900ng/mL, 4950 ng/mL, 5000 ng/mL, 5050 ng/mL, 5100 ng/mL, 5150 ng/mL, 5200ng/mL, 5250 ng/mL, 5300 ng/mL, 5350 ng/mL, 5400 ng/mL, 5450 ng/mL, 5500ng/mL, 5550 ng/mL, 5600 ng/mL, 5650 ng/mL, 5700 ng/mL, 5750 ng/mL, 5800ng/mL, 5850 ng/mL, 5900 ng/mL, 5950 ng/mL, 6000 ng/mL, 6050 ng/mL, 6100ng/mL, 6150 ng/mL, 6200 ng/mL, 6250 ng/mL, 6300 ng/mL, 6350 ng/mL, 6400ng/mL, 6450 ng/mL, 6500 ng/mL, 6550 ng/mL, 6600 ng/mL, 6650 ng/mL, 6700ng/mL, 6750 ng/mL, 6800 ng/mL, 6850 ng/mL, 6900 ng/mL, 6950 ng/mL, 7000ng/mL, 7050 ng/mL, 7100 ng/mL, 7150 ng/mL, 7200 ng/mL, 7250 ng/mL, 7300ng/mL, 7350 ng/mL, 7400 ng/mL, 7450 ng/mL, 7500 ng/mL, 7550 ng/mL, 7600ng/mL, 7650 ng/mL, 7700 ng/mL, 7750 ng/mL, 7800 ng/mL, 7850 ng/mL, 7900ng/mL, 7950 ng/mL, 8000 ng/mL, 8050 ng/mL, 8100 ng/mL, 8150 ng/mL, 8200ng/mL, 8250 ng/mL, 8300 ng/mL, 8350 ng/mL, 8400 ng/mL, 8450 ng/mL, 8500ng/mL, 8550 ng/mL, 8600 ng/mL, 8650 ng/mL, 8700 ng/mL, 8750 ng/mL, 800ng/mL, 8850 ng/mL, 8900 ng/mL, 8950 ng/mL, 9000 ng/mL, 9050 ng/mL, 9100ng/mL, 9150 ng/mL, 9200 ng/mL, 9250 ng/mL, 9300 ng/mL, 9350 ng/mL, 9400ng/mL, 9450 ng/mL, 9500 ng/mL, 9550 ng/mL, 9600 ng/mL, 9650 ng/mL, 9700ng/mL, 9750 ng/mL, 9000 ng/mL, 9950 ng/mL, 9900 ng/mL, 9950 ng/mL, 10000ng/mL, 10050 ng/mL, 10100 ng/mL, 10150 ng/mL, 10200 ng/mL, 10250 ng/mL,10300 ng/mL, 10350 ng/mL, 10400 ng/mL, 10450 ng/mL, 10500 ng/mL, 10550ng/mL, 10600 ng/mL, 10650 ng/mL, 10700 ng/mL, 10750 ng/mL, 1000 ng/mL,101050 ng/mL, 10900 ng/mL, 10950 ng/mL, 11000 ng/mL, 11050 ng/mL, 11100ng/mL, 11150 ng/mL, 11200 ng/mL, 11250 ng/mL, 11300 ng/mL, 11350 ng/mL,11400 ng/mL, 11450 ng/mL, 11500 ng/mL, 11550 ng/mL, 11600 ng/mL, 11650ng/mL, 11700 ng/mL, 11750 ng/mL, 1100 ng/mL, 111150 ng/mL, 11900 ng/mL,11950 ng/mL, 12000 ng/mL, 12050 ng/mL, 12100 ng/mL, 12150 ng/mL, 12200ng/mL, 12250 ng/mL, 12300 ng/mL, 12350 ng/mL, 12400 ng/mL, 12450 ng/mL,12500 ng/mL, 12550 ng/mL, 12600 ng/mL, 12650 ng/mL, 12700 ng/mL, 12750ng/mL, 1200 ng/mL, 121250 ng/mL, 12900 ng/mL, 12950 ng/mL, 13000 ng/mL,13050 ng/mL, 13100 ng/mL, 13150 ng/mL, 13200 ng/mL, 13250 ng/mL, 13300ng/mL, 13350 ng/mL, 13400 ng/mL, 13450 ng/mL, 13500 ng/mL, 13550 ng/mL,13600 ng/mL, 13650 ng/mL, 13700 ng/mL, 13750 ng/mL, 1300 ng/mL, 131350ng/mL, 13900 ng/mL, 13950 ng/mL, 14000 ng/mL, 14050 ng/mL, 14100 ng/mL,14150 ng/mL, 14200 ng/mL, 14250 ng/mL, 14300 ng/mL, 14350 ng/mL, 14400ng/mL, 14450 ng/mL, 14500 ng/mL, 14550 ng/mL, 14600 ng/mL, 14650 ng/mL,14700 ng/mL, 14750 ng/mL, 1400 ng/mL, 141450 ng/mL, 14900 ng/mL, 14950ng/mL, 15000 ng/mL, 15050 ng/mL, 15100 ng/mL, 15150 ng/mL, 15200 ng/mL,15250 ng/mL, 15300 ng/mL, 15350 ng/mL, 15400 ng/mL, 15450 ng/mL, 15500ng/mL, 15550 ng/mL, 15600 ng/mL, 15650 ng/mL, 15700 ng/mL, 15750 ng/mL,1500 ng/mL, 151550 ng/mL, 15900 ng/mL, 15950 ng/mL, 16000 ng/mL, 16050ng/mL, 16100 ng/mL, 16150 ng/mL, 16200 ng/mL, 16250 ng/mL, 16300 ng/mL,16350 ng/mL, 16400 ng/mL, 16450 ng/mL, 16500 ng/mL, 16550 ng/mL, 16600ng/mL, 16650 ng/mL, 16700 ng/mL, 16750 ng/mL, 1600 ng/mL, 161650 ng/mL,16900 ng/mL, 16950 ng/mL, 17000 ng/mL, 17050 ng/mL, 17100 ng/mL, 17150ng/mL, 17200 ng/mL, 17250 ng/mL, 17300 ng/mL, 17350 ng/mL, 17400 ng/mL,17450 ng/mL, 17500 ng/mL, 17550 ng/mL, 17600 ng/mL, 17650 ng/mL, 17700ng/mL, 17750 ng/mL, 1700 ng/mL, 171750 ng/mL, 17900 ng/mL, 17950 ng/mL,or 18000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the propofolplasma AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered or the propofol patient populationmean AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered is, at least any one of 0.5ng*h/mL/mg, 0.55 ng*h/mL/mg, 0.6 ng*h/mL/mg, 0.65 ng*h/mL/mg, 0.7ng*h/mL/mg, 0.75 ng*h/mL/mg, 0.8 ng*h/mL/mg, 0.85 ng*h/mL/mg, 0.9ng*h/mL/mg, 0.95 ng*h/mL/mg, 1.0 ng*h/mL/mg, 1.05 ng*h/mL/mg, 1.10ng*h/mL/mg, 1.15 ng*h/mL/mg, 1.2 ng*h/mL/mg, 1.25 ng*h/mL/mg, 1.3ng*h/mL/mg, 1.35 ng*h/mL/mg, 1.4 ng*h/mL/mg, 1.45 ng*h/mL/mg, 1.5ng*h/mL/mg, 1.55 ng*h/mL/mg, 1.6 ng*h/mL/mg, 1.65 ng*h/mL/mg, or 1.7ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient is headache free, has experienced a reductionin headache pain, is no longer experiencing a most bothersome symptom,or is no longer experiencing a bothersome symptom and the fospropofolplasma AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered or the fospropofol patient populationmean AUC_(0-∞) per mg of fospropofol (or a pharmaceutically acceptablesalt of fospropofol) administered is at least 3.0 ng*h/mL, such as, forexample, at least any one of 3.0 ng*h/mL/mg, 3.1 ng*h/mL/mg, 3.2ng*h/mL/mg, 3.3 ng*h/mL/mg, 3.4 ng*h/mL/mg, 3.5 ng*h/mL/mg, 3.6ng*h/mL/mg, 3.7 ng*h/mL/mg, 3.8 ng*h/mL/mg, 3.9 ng*h/mL/mg, 4.0ng*h/mL/mg, 4.1 ng*h/mL/mg, 4.2 ng*h/mL/mg, 4.3 ng*h/mL/mg, 4.4ng*h/mL/mg, 4.5 ng*h/mL/mg, 4.6 ng*h/mL/mg, 4.7 ng*h/mL/mg, 4.8ng*h/mL/mg, 4.9 ng*h/mL/mg, 5.0 ng*h/mL/mg, 5.1 ng*h/mL/mg, 5.2ng*h/mL/mg, 5.3 ng*h/mL/mg, 5.4 ng*h/mL/mg, 5.5 ng*h/mL/mg, 5.6ng*h/mL/mg, 5.7 ng*h/mL/mg, 5.8 ng*h/mL/mg, 5.9 ng*h/mL/mg, 6.0ng*h/mL/mg, 6.1 ng*h/mL/mg, 6.2 ng*h/mL/mg, 6.3 ng*h/mL/mg, 6.4ng*h/mL/mg, 6.5 ng*h/mL/mg, 6.6 ng*h/mL/mg, 6.7 ng*h/mL/mg, 6.8ng*h/mL/mg, 6.9 ng*h/mL/mg, 7.0 ng*h/mL/mg, 7.1 ng*h/mL/mg, 7.2ng*h/mL/mg, 7.3 ng*h/mL/mg, 7.4 ng*h/mL/mg, 7.5 ng*h/mL/mg. 7.6ng*h/mL/mg, 7.7 ng*h/mL/mg, 7.8 ng*h/mL/mg, 7.9 ng*h/mL/mg, 8.0ng*h/mL/mg, 8.1 ng*h/mL/mg, 8.2 ng*h/mL/mg, 8.3 ng*h/mL/mg, 8.4ng*h/mL/mg, 8.5 ng*h/mL/mg, 8.6 ng*h/mL/mg, 8.7 ng*h/mL/mg, 8.8ng*h/mL/mg, 8.9 ng*h/mL/mg, or 9.0 ng*h/mL/mg.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol AUC_(4hr) or thepatient population has a mean AUC_(4hr) of at least 1000 ng*h/mL, suchas, for example, at least 1000 ng*h/mL, at least 1050 ng*h/mL, at least1100 ng*h/mL, at least 1150 ng*h/mL, at least 1200 ng*h/mL, at least1250 ng*h/mL, at least 1300 ng*h/mL, at least 1350 ng*h/mL, at least1400 ng*h/mL, at least 1450 ng*h/mL, at least 1500 ng*h/mL, at least1550 ng*h/mL, at least 1600 ng*h/mL, at least 1650 ng*h/mL, at least1700 ng*h/mL, at least 1750 ng*h/mL, at least 1800 ng*h/mL, at least1850 ng*h/mL, at least 1900 ng*h/mL, at least 1950 ng*h/mL, at least2000 ng*h/mL, at least 2050 ng*h/mL, at least 2100 ng*h/mL, at least2150 ng*h/mL, at least 2200 ng*h/mL, at least 2250 ng*h/mL, at least2300 ng*h/mL, at least 2350 ng*h/mL, at least 2400 ng*h/mL, at least2450 ng*h/mL, at least 2500 ng*h/mL, at least 2550 ng*h/mL, at least2600 ng*h/mL, at least 2650 ng*h/mL, at least 2700 ng*h/mL, at least2750 ng*h/mL, at least 2800 ng*h/mL, at least 2850 ng*h/mL, at least2900 ng*h/mL, at least 2950 ng*h/mL, at least 3000 ng*h/mL, at least3050 ng*h/mL, at least 3100 ng*h/mL, at least 3150 ng*h/mL, at least3200 ng*h/mL, at least 3250 ng*h/mL, at least 3300 ng*h/mL, at least3350 ng*h/mL, at least 3400 ng*h/mL, at least 3450 ng*h/mL, at least3500 ng*h/mL, at least 3550 ng*h/mL, at least 3600 ng*h/mL, at least3650 ng*h/mL, at least 3700 ng*h/mL, at least 3750 ng*h/mL, at least3800 ng*h/mL, at least 3850 ng*h/mL, at least 3900 ng*h/mL, at least3950 ng*h/mL, at least 4000 ng*h/mL, at least 4050 ng*h/mL, at least4100 ng*h/mL, at least 4150 ng*h/mL, at least 4200 ng*h/mL, at least4250 ng*h/mL, at least 4300 ng*h/mL, at least 4350 ng*h/mL, at least4400 ng*h/mL, at least 4450 ng*h/mL, at least 4500 ng*h/mL, at least4550 ng*h/mL, at least 4600 ng*h/mL, at least 4650 ng*h/mL, at least4700 ng*h/mL, at least 4750 ng*h/mL, at least 4800 ng*h/mL, at least4850 ng*h/mL, at least 4900 ng*h/mL, at least 4950 ng*h/mL, at least5000 ng*h/mL, at least 5050 ng*h/mL, at least 5100 ng*h/mL, at least5150 ng*h/mL, at least 5200 ng*h/mL, at least 5250 ng*h/mL, at least5300 ng*h/mL, at least 5350 ng*h/mL, at least 5400 ng*h/mL, at least5450 ng*h/mL, at least 5500 ng*h/mL, at least 5550 ng*h/mL, at least5600 ng*h/mL, at least 5650 ng*h/mL, at least 5700 ng*h/mL, at least5750 ng*h/mL, at least 5800 ng*h/mL, at least 5850 ng*h/mL, at least5900 ng*h/mL, at least 5950 ng*h/mL, at least 6000 ng*h/mL, at least6050 ng*h/mL, at least 6100 ng*h/mL, at least 6150 ng*h/mL, at least6200 ng*h/mL, at least 6250 ng*h/mL, at least 6300 ng*h/mL, at least6350 ng*h/mL, at least 6400 ng*h/mL, at least 6450 ng*h/mL, at least6500 ng*h/mL, at least 6550 ng*h/mL, at least 6600 ng*h/mL, at least6650 ng*h/mL, at least 6700 ng*h/mL, at least 6750 ng*h/mL, at least6800 ng*h/mL, at least 6850 ng*h/mL, at least 6900 ng*h/mL, at least6950 ng*h/mL, at least 7000 ng*h/mL, at least 7050 ng*h/mL, at least7100 ng*h/mL, at least 7150 ng*h/mL, at least 7200 ng*h/mL, at least7250 ng*h/mL, at least 7300 ng*h/mL, at least 7350 ng*h/mL, at least7400 ng*h/mL, at least 7450 ng*h/mL, at least 7500 ng*h/mL, at least7550 ng*h/mL, at least 7600 ng*h/mL, at least 7650 ng*h/mL, at least7700 ng*h/mL, at least 7750 ng*h/mL, at least 7800 ng*h/mL, at least7850 ng*h/mL, at least 7900 ng*h/mL, at least 7950 ng*h/mL, at least8000 ng*h/mL, at least 8050 ng*h/mL, at least 8100 ng*h/mL, at least8150 ng*h/mL, at least 8200 ng*h/mL, at least 8250 ng*h/mL, at least8300 ng*h/mL, at least 8350 ng*h/mL, at least 8400 ng*h/mL, at least8450 ng*h/mL, at least 8500 ng*h/mL, at least 8550 ng*h/mL, at least8600 ng*h/mL, at least 8650 ng*h/mL, at least 8700 ng*h/mL, at least8750 ng*h/mL, at least 8800 ng*h/mL, at least 8850 ng*h/mL, at least8900 ng*h/mL, at least 8950 ng*h/mL, at least 9000 ng*h/mL, at least9050 ng*h/mL, at least 9100 ng*h/mL, at least 9150 ng*h/mL, at least9200 ng*h/mL, at least 9250 ng*h/mL, at least 9300 ng*h/mL, at least9350 ng*h/mL, at least 9400 ng*h/mL, at least 9450 ng*h/mL, at least9500 ng*h/mL, at least 9550 ng*h/mL, at least 9600 ng*h/mL, at least9650 ng*h/mL, at least 9700 ng*h/mL, at least 9750 ng*h/mL, at least9800 ng*h/mL, at least 9850 ng*h/mL, at least 9900 ng*h/mL, at least9950 ng*h/mL, or at least 10000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol AUC_(4hr) or thepatient population has a mean AUC_(4hr) as set forth herein and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol AUC_(4hr) or thepatient population has a mean AUC_(4hr) of at least 1000 ng*h/mL and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol AUC_(4hr) or thepatient population has a mean AUC_(4hr) as set forth herein and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol AUC_(4hr) or thepatient population has a mean AUC_(4hr) of at least 1000 ng*h/mL and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol AUC_(4hr) or thepatient population has a mean AUC_(4hr) as set forth herein and thepatient is no longer experiencing its most bothersome symptom. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol AUC_(4hr) or thepatient population has a mean AUC_(4hr) of at least 1000 ng*h/mL and thepatient is no longer experiencing its most bothersome symptom (MBS). Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hour after theadministration the patient has plasma fospropofol concentration(C_(4hr)) or the patient population has a mean C_(4hr) of 0 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has a plasma fospropofol concentration(C_(4hr)) or the patient population has a mean C_(4hr) as set forthherein and the patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol concentration(C_(4hr)) or the patient population has a mean C_(4hr) of 0 ng/mL andthe patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol concentration(C_(4hr)) or the patient population has a mean C_(4hr) as set forthherein and the patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol concentration(C_(4hr)) or the patient population has a mean C_(4hr) of 0 ng/mL andthe patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol concentration(C_(4hr)) or the patient population has a mean C_(4hr) as set forthherein and the patient is no longer experiencing its most bothersomesymptom. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea, photophobia, orphonophobia. In some embodiments, the MBS is nausea. In someembodiments, the MBS is photophobia. In some embodiments, the MBS isphonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma fospropofol concentration(C_(4hr)) or the patient population has a mean C_(4hr) of 0 ng/mL andthe patient is no longer experiencing its most bothersome symptom (MBS).In some embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol AUC_(1hr) or the patientpopulation has a mean AUC_(1hr) of at least at least 25 ng*h/mL, suchas, for example, at least 25 ng*h/mL, at least 50 ng*h/mL, at least 75ng*h/mL, at least 100 ng*h/mL, at least 125 ng*h/mL, at least 150ng*h/mL, at least 175 ng*h/mL, at least 200 ng*h/mL, at least 225ng*h/mL, at least 250 ng*h/mL, 275 ng*h/mL, at least 300 ng*h/mL, atleast 325 ng*h/mL, at least 350 ng*h/mL, at least 400 ng*h/mL, at least425 ng*h/mL, at least 450 ng*h/mL, at least 475 ng*h/mL, at least 500ng*h/mL, at least 525 ng*h/mL, at least 550 ng*h/mL, at least 575ng*h/mL, at least 600 ng*h/mL, at least 625 ng*h/mL, at least 650ng*h/mL, at least 675 ng*h/mL, at least 700 ng*h/mL, at least 725ng*h/mL, at least 750 ng*h/mL, at least 775 ng*h/mL, at least 800ng*h/mL, at least 825 ng*h/mL, at least 850 ng*h/mL, at least 875ng*h/mL, at least 900 ng*h/mL, at least 925 ng*h/mL, at least 950ng*h/mL, at least 975 ng*h/mL, or at least 1000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol AUC_(1hr) or the patientpopulation has a mean AUC_(1hr) as set forth herein and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol AUC_(1hr) or the patientpopulation has a mean AUC_(1hr) of at least 250 ng*h/mL and the patientis headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol AUC_(1hr) or the patientpopulation has a mean AUC_(1hr) as set forth herein and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol AUC_(1hr) or the patientpopulation has a mean AUC_(1hr) of at least 50 ng*h/mL and the patienthas experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol AUC_(1hr) or the patientpopulation has a mean AUC_(1hr) as set forth herein and the patient isno longer experiencing its most bothersome symptom. In some embodiments,the MBS is nausea, photophobia, or phonophobia. In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol AUC_(1hr) or the patientpopulation has a mean AUC_(1hr) of at least 50 ng*h/mL and the patientis no longer experiencing its most bothersome symptom (MBS). In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol concentration (C_(1hr))or the patient population has a mean C_(1hr) of at least 25 ng/mL, suchas, for example, at least 25 ng/mL, at least 50 ng/mL, at least 75ng/mL, at least 100 ng/mL, at least 125 ng/mL, at least 150 ng/mL, atleast 175 ng/mL, at least 200 ng/mL, at least 225 ng/mL, at least 250ng/mL, 275 ng/mL, at least 300 ng/mL, at least 325 ng/mL, at least 350ng/mL, at least 400 ng/mL, at least 425 ng/mL, at least 450 ng/mL, atleast 475 ng/mL, at least 500 ng/mL, at least 525 ng/mL, at least 550ng/mL, at least 575 ng/mL, at least 600 ng/mL, at least 625 ng/mL, atleast 650 ng/mL, at least 675 ng/mL, at least 700 ng/mL, at least 725ng/mL, at least 750 ng/mL, at least 775 ng/mL, at least 800 ng/mL, atleast 825 ng/mL, at least 850 ng/mL, at least 875 ng/mL, at least 900ng/mL, at least 925 ng/mL, at least 950 ng/mL, at least 975 ng/mL, or atleast 1000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has a plasma propofol concentration (C_(1hr))or the patient population has a mean C_(1hr) as set forth herein and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol concentration (C_(1hr))or the patient population has a mean C_(1hr) of at least 500 ng/mL andthe patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol concentration (C_(1hr))or the patient population has a mean C_(1hr) as set forth herein and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol concentration (C_(1hr))or the patient population has a mean C_(1hr) of at least 90 ng/mL andthe patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol concentration (C_(1hr))or the patient population has a mean C_(1hr) as set forth herein and thepatient is no longer experiencing its most bothersome symptom. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 1 hour after theadministration the patient has plasma propofol concentration (C_(1hr))or the patient population has a mean C_(1hr) of at least 90 ng/mL andthe patient is no longer experiencing its most bothersome symptom (MBS).In some embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol AUC_(2hr) or the patientpopulation has a mean AUC_(2hr) of at least at least 25 ng*h/mL, suchas, for example, at least 25 ng*h/mL, at least 50 ng*h/mL, at least 75ng*h/mL, at least 100 ng*h/mL, at least 125 ng*h/mL, at least 150ng*h/mL, at least 175 ng*h/mL, at least 200 ng*h/mL, at least 225ng*h/mL, at least 250 ng*h/mL, 275 ng*h/mL, at least 300 ng*h/mL, atleast 325 ng*h/mL, at least 350 ng*h/mL, at least 400 ng*h/mL, at least425 ng*h/mL, at least 450 ng*h/mL, at least 475 ng*h/mL, at least 500ng*h/mL, at least 525 ng*h/mL, at least 550 ng*h/mL, at least 575ng*h/mL, at least 600 ng*h/mL, at least 625 ng*h/mL, at least 650ng*h/mL, at least 675 ng*h/mL, at least 700 ng*h/mL, at least 725ng*h/mL, at least 750 ng*h/mL, at least 775 ng*h/mL, at least 800ng*h/mL, at least 825 ng*h/mL, at least 850 ng*h/mL, at least 875ng*h/mL, at least 900 ng*h/mL, at least 925 ng*h/mL, at least 950ng*h/mL, at least 975 ng*h/mL, or at least 1000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol AUC_(2hr) or the patientpopulation has a mean AUC_(2hr) as set forth herein and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol AUC_(2hr) or the patientpopulation has a mean AUC_(2hr) of at least 100 ng*h/mL and the patientis headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol AUC_(2hr) or the patientpopulation has a mean AUC_(2hr) as set forth herein and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol AUC_(2hr) or the patientpopulation has a mean AUC_(2hr) of at least 90 ng*h/mL and the patienthas experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol AUC_(2hr) or the patientpopulation has a mean AUC_(2hr) as set forth herein and the patient isno longer experiencing its most bothersome symptom. In some embodiments,the MBS is nausea, photophobia, or phonophobia. In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol AUC_(2hr) or the patientpopulation has a mean AUC_(2hr) of at least 40 ng*h/mL and the patientis no longer experiencing its most bothersome symptom (MBS). In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol concentration (C_(2hr))or the patient population has a mean C_(2hr) of at least 25 ng/mL, suchas, for example, at least 25 ng/mL, at least 50 ng/mL, at least 75ng/mL, at least 100 ng/mL, at least 125 ng/mL, at least 150 ng/mL, atleast 175 ng/mL, at least 200 ng/mL, at least 225 ng/mL, at least 250ng/mL, 275 ng/mL, at least 300 ng/mL, at least 325 ng/mL, at least 350ng/mL, at least 400 ng/mL, at least 425 ng/mL, at least 450 ng/mL, atleast 475 ng/mL, at least 500 ng/mL, at least 525 ng/mL, at least 550ng/mL, at least 575 ng/mL, at least 600 ng/mL, at least 625 ng/mL, atleast 650 ng/mL, at least 675 ng/mL, at least 700 ng/mL, at least 725ng/mL, at least 750 ng/mL, at least 775 ng/mL, at least 800 ng/mL, atleast 825 ng/mL, at least 850 ng/mL, at least 875 ng/mL, at least 900ng/mL, at least 925 ng/mL, at least 950 ng/mL, at least 975 ng/mL, or atleast 1000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hour after theadministration the patient has a plasma propofol concentration (C_(2hr))or the patient population has a mean C_(2hr) as set forth herein and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol concentration (C_(2hr))or the patient population has a mean C_(2hr) of at least 40 ng/mL andthe patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hour after theadministration the patient has plasma propofol concentration (C_(2hr))or the patient population has a mean C_(2hr) as set forth herein and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol concentration (C_(2hr))or the patient population has a mean C_(2hr) of at least 40 ng/mL andthe patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol concentration (C_(2hr))or the patient population has a mean C_(2hr) as set forth herein and thepatient is no longer experiencing its most bothersome symptom. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 2 hours after theadministration the patient has plasma propofol concentration (C_(2hr))or the patient population has a mean C_(2hr) of at least 20 ng/mL andthe patient is no longer experiencing its most bothersome symptom (MBS).In some embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol AUC_(4hr) or the patientpopulation has a mean AUC_(4hr) of at least at least 25 ng*h/mL, suchas, for example, at least 25 ng*h/mL, at least 50 ng*h/mL, at least 75ng*h/mL, at least 100 ng*h/mL, at least 125 ng*h/mL, at least 150ng*h/mL, at least 175 ng*h/mL, at least 200 ng*h/mL, at least 225ng*h/mL, at least 250 ng*h/mL, 275 ng*h/mL, at least 300 ng*h/mL, atleast 325 ng*h/mL, at least 350 ng*h/mL, at least 400 ng*h/mL, at least425 ng*h/mL, at least 450 ng*h/mL, at least 475 ng*h/mL, at least 500ng*h/mL, at least 525 ng*h/mL, at least 550 ng*h/mL, at least 575ng*h/mL, at least 600 ng*h/mL, at least 625 ng*h/mL, at least 650ng*h/mL, at least 675 ng*h/mL, at least 700 ng*h/mL, at least 725ng*h/mL, at least 750 ng*h/mL, at least 775 ng*h/mL, at least 800ng*h/mL, at least 825 ng*h/mL, at least 850 ng*h/mL, at least 875ng*h/mL, at least 900 ng*h/mL, at least 925 ng*h/mL, at least 950ng*h/mL, at least 975 ng*h/mL, or at least 1000 ng*h/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol AUC_(4hr) or the patientpopulation has a mean AUC_(4hr) as set forth herein and the patient isheadache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol AUC_(4hr) or the patientpopulation has a mean AUC_(4hr) of at least 150 ng*h/mL and the patientis headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol AUC_(4hr) or the patientpopulation has a mean AUC_(4hr) as set forth herein and the patient hasexperienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol AUC_(4hr) or the patientpopulation has a mean AUC_(4hr) of at least 150 ng*h/mL and the patienthas experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol AUC_(4hr) or the patientpopulation has a mean AUC_(4hr) as set forth herein and the patient isno longer experiencing its most bothersome symptom. In some embodiments,the MBS is nausea, photophobia, or phonophobia. In some embodiments, theMBS is nausea, photophobia, or phonophobia. In some embodiments, the MBSis nausea. In some embodiments, the MBS is photophobia. In someembodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol AUC_(4hr) or the patientpopulation has a mean AUC_(4hr) of at least 100 ng*h/mL and the patientis no longer experiencing its most bothersome symptom (MBS). In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hour after theadministration the patient has plasma propofol concentration (C_(4hr))or the patient population has a mean C_(4hr) of at least 5 ng/mL, suchas, for example, at least 5 ng/mL, at least 10 ng/mL, at least 15 ng/mL,at least 20 ng/mL, at least 25 ng/mL, at least 50 ng/mL, at least 75ng/mL, at least 100 ng/mL, at least 125 ng/mL, at least 150 ng/mL, atleast 175 ng/mL, at least 200 ng/mL, at least 225 ng/mL, at least 250ng/mL, 275 ng/mL, at least 300 ng/mL, at least 325 ng/mL, at least 350ng/mL, at least 400 ng/mL, at least 425 ng/mL, at least 450 ng/mL, atleast 475 ng/mL, at least 500 ng/mL, at least 525 ng/mL, at least 550ng/mL, at least 575 ng/mL, at least 600 ng/mL, at least 625 ng/mL, atleast 650 ng/mL, at least 675 ng/mL, at least 700 ng/mL, at least 725ng/mL, at least 750 ng/mL, at least 775 ng/mL, at least 800 ng/mL, atleast 825 ng/mL, at least 850 ng/mL, at least 875 ng/mL, at least 900ng/mL, at least 925 ng/mL, at least 950 ng/mL, at least 975 ng/mL, or atleast 1000 ng/mL.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has a plasma propofol concentration (C_(4hr))or the patient population has a mean C_(4hr) as set forth herein and thepatient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol concentration (C_(4hr))or the patient population has a mean C_(4hr) of at least 10 ng/mL andthe patient is headache free.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol concentration (C_(4hr))or the patient population has a mean C_(4hr) as set forth herein and thepatient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol concentration (C_(4hr))or the patient population has a mean C_(4hr) of at least 10 ng/mL andthe patient has experienced a reduction in headache pain.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol concentration (C_(4hr))or the patient population has a mean C_(4hr) as set forth herein and thepatient is no longer experiencing its most bothersome symptom. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea, photophobia, or phonophobia. In someembodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

In some aspects, the disclosure is directed to methods of treatingmigraine in a patient or patient population in need thereof, wherein themethods comprise administering to the patient(s) a pharmaceuticalcomposition of the disclosure, wherein at 4 hours after theadministration the patient has plasma propofol concentration (C_(4hr))or the patient population has a mean C_(4hr) of at least 10 ng/mL andthe patient is no longer experiencing its most bothersome symptom (MBS).In some embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea, photophobia, or phonophobia. Insome embodiments, the MBS is nausea. In some embodiments, the MBS isphotophobia. In some embodiments, the MBS is phonophobia.

Acidified Pharmaceutical Dosage Forms

In some aspects, the pharmaceutical compositions of the disclosure arepharmaceutical dosage forms for oral administration comprisingfospropofol or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable acid. Such pharmaceutical compositions maybe referred to herein as “acidified pharmaceutical dosage forms.”

In some embodiments, the methods of treatment disclosed herein areperformed using the acidified pharmaceutical dosage forms.

In some embodiments, the acidified pharmaceutical dosage forms comprisefospropofol:

In other embodiments, the acidified pharmaceutical dosage forms comprisea pharmaceutically acceptable salt of fospropofol.

In some embodiments, the pharmaceutically acceptable salt of fospropofolis a potassium, diethylamine, t-butylamine, ethylene diamine,benzathine, piperazine, ethanolamine, diethanolamine, ammonium,tromethamine, benethamine, histidine, calcium, magnesium, or zinc salt.

In some embodiments, the acidified pharmaceutical dosage forms comprisefospropofol disodium:

The acidified pharmaceutical dosage forms of the disclosure including apharmaceutically acceptable salt of fospropofol comprise apharmaceutically acceptable acid. Pharmaceutically acceptable acids areknown in the art. Exemplary pharmaceutically acceptable acids includeall applicable stereoisomers including diastereomers, enantiomers andmixtures thereof, for example, 1-hydroxy-2-naphthoic acid,2,2-dichloroacetic acid, 2-hydroxethanesulfonic acid, 4-acetamidobenzoicacid, 4-aminosalicyclic acid, acetic acid, aceturic acid, Acidhydrolyzed proteins, Acid Modified Starch, Aconitic Acid, adipic acid,alginic acid, a-oxo-glutaric acid, benzenesulfonic acid, benzoic acid,butyric acid, camphor-10-sulfonic acid, camphoric acid, capric acid,caproic acid, caprylic acid, carbonic acid, Cholic acid, cinnamic acid,citric acid, cyclamic acid, D(−)-Lactic acid, Desoxycholic acid,D-glucaric acid, D-glucoheptonic acid, D-glucuronic acid,Di(tert-butyl)naphthalenedisulfonic acid,Di(tert-butyl)naphthalenesulfonic acid, DL-lactic acid, DL-mandelicacid, DL-tartaric acid, tartaric acid, dodecylsulfuric acid, Erythorbicacid (D-isoascorbic acid), ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, fumaric acid, galactaric acid, gentisic acid,glutaric acid, glycerophosphoric acid, Glycocholic acid, glycolic acid,hexanedioic acid, hippuric acid, hydrobromic acid, Hydrochloric acid,Iron naphthenate, iron salts, iron salts, isobutyric acid, L(+)-lacticacid, L(+)-potassium acid tartrate, tartaric acid, L(+)-tartaric acid,Lactic acid, lactobionic acid, L-ascorbic acid, ascorbic acid,L-aspartic acid, lauric acid, L-glutamic acid, L-Glutamic acidhydrochloride, Linoleic acid, L-Malic acid, L-pyroglutamic acid,L-tartaric acid, maleic acid, malic acid, malonic acid, methanesulfonicacid, monobasic potassium phosphate, monobasic sodium phosphate,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, naphthenicacids, Niacin (nicotinic acid), nicotinic acid, nitric acid, octanoicacid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,Pectin low acid, Pectinic acid, phosphoric acid, propanoic acid,Propionic acid, p-toluenesulfonic acid, pyruvic acid, saccharin,salicylic acid, sebacic acid, Sodium acid pyrophosphate, Sodium aluminumphosphate, sodium metabisulfite, Sorbic acid, stearic acid, succinicacid, sulfuric acid, tall oil fatty acids, Tannic acid (hydrolyzablegallotannins), Taurocholic acid, thiocyanic acid, Thiodipropionic acid,trifluoroacetic acid, undec-10-enoic acid, orange juice, apple juice,grapefruit juice, as well as combinations thereof. As used herein, a“pharmaceutically acceptable acid” preferably refers to an acid that ison the FDA published inactive ingredient database (IID) for approveddrug products or the generally recognized as safe (GRAS) database foruse in food. In some embodiments, the pharmaceutically acceptable acidis a polyacid such as hyaluronic acid, polyacrylic acid (e.g.,Carbomers), polyaspartic acid, polyglutamic acid or mixtures thereof.

In some embodiments, the pharmaceutically acceptable acid is ascorbicacid, citric acid, malic acid, tartaric acid, succinic acid, fumaricacid, maleic acid, lactic acid, monobasic sodium phosphate, monobasicpotassium phosphate, or sodium metabisulfite.

In other embodiments, the pharmaceutically acceptable acid is ascorbicacid, citric acid, malic acid, or tartaric acid, or all applicablestereoisomers including diastereomers, enantiomers and mixtures thereof.

In some embodiments, the pharmaceutically acceptable acid is ascorbicacid. As used herein, the term “ascorbic acid” refers to DL-ascorbicacid, L-ascorbic acid, D-ascorbic acid, or mixtures thereof. In someembodiments, the ascorbic acid is DL-ascorbic acid. In otherembodiments, the ascorbic acid is L-ascorbic acid. In other embodiments,the ascorbic acid is D-ascorbic acid.

In some embodiments, the pharmaceutically acceptable acid is tartaricacid. As used herein, the term “tartaric acid” refers to DL-tartaricacid, L-tartaric acid, D-tartaric acid, meso-tartaric acid, or mixturesthereof. In some embodiments, the tartaric acid is DL-tartaric acid. Inother embodiments, the tartaric acid is L-tartaric acid. In otherembodiments, the tartaric acid is D-tartaric acid.

In some embodiments, the pharmaceutically acceptable acid is malic acid.As used herein, the term “malic acid” refers to DL-malic acid, L-malicacid, D-malic acid, or mixtures thereof. In some embodiments, the malicacid is DL-malic acid. In other embodiments, the malic acid is L-malicacid. In other embodiments, the malic acid is D-malic acid.

In some embodiments, the pharmaceutically acceptable acid is citricacid.

In some embodiments, the pharmaceutically acceptable acid is fumaricacid, i.e., the trans isomer of butenedioic acid. In some embodiments,the pharmaceutically acceptable acid is maleic acid, i.e., the cisisomer of butenedioic acid. In some embodiments, the pharmaceuticallyacceptable acid is a mixture of the cis isomer of butenedioic acid andthe trans isomer of butenedioic acid. An exemplary compositioncomprising fumaric acid comprises 384.2 mg fospropofol disodium hydrate(equivalent to 300 mg fospropofol disodium), 28.2 mg of polyplasdone XL,2.8 mg of magnesium stearate, and 150.0 mg of fumaric acid. Anotherexemplary composition comprising fumaric acid comprises 127.8 mgfospropofol disodium hydrate (equivalent to 100 mg fospropofoldisodium), 14.7 mg of polyplasdone XL, 1.46 mg of magnesium stearate,and 150.0 mg of fumaric acid.

In some embodiments in which the acidified pharmaceutical dosage formsof the disclosure comprise fospropofol in acid form, i.e.,

the dosage forms do not include an additional pharmaceuticallyacceptable acid because in such embodiments, the fospropofol acid itselfprovides the acidity to achieve oral bioavailability and/or reducedinter-subject variability.

In some aspects, the acidified pharmaceutical dosage forms furthercomprise a pharmaceutically acceptable excipient. In such aspects, thepharmaceutically acceptable excipient is present in addition to thepharmaceutically acceptable acid. Examples of pharmaceuticallyacceptable excipients were disclosed previously herein.

In some embodiments, the fospropofol (or pharmaceutically acceptablesalt thereof) and the pharmaceutically acceptable acid can be present inthe same unit dosage form. In other embodiments, all or a portion of thepharmaceutically acceptable acid can be administered separately from theunit dosage form comprising the fospropofol (or pharmaceuticallyacceptable salt thereof).

In some aspects, the acidified pharmaceutical dosage forms are thosethat when dissolved in water, contain an amount of pharmaceuticallyacceptable acid necessary to drive the ionic equilibrium of the aqueoussolution towards a pH lower than 7 and preferably ≤4.5.

In some aspects, the acidified pharmaceutical dosage forms are thosewherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 6.3, such as, for example,a pH of less than or equal to 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6,5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2,4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8,2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4,1.3, 1.2, 1.1, or 1.0.

In some embodiments, a therapeutically effective amount of fospropofol,or a pharmaceutically acceptable salt of fospropofol, is 10-4800 mg (ona fospropofol basis), for example, an amount that is about (i.e., thespecified number±10%) any one of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg,850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg,1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg,1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg,2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg,2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg,2850 mg, 2900 mg, 2950 mg, 3000 mg, 2050 mg, 3100 mg, 3150 mg, 3200 mg,3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg,3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg,4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg,4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, or 4800mg.

In other embodiments, a therapeutically effective amount of fospropofol,or a pharmaceutically acceptable salt of fospropofol, is about 1 mg/kgto about 80 mg/kg (on a fospropofol basis), for example, an amount thatis about (i.e., the specified number±10%) any one of 1 mg/kg, 2 mg/kg, 3mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg,11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32mg/kg, 33 mg/kg, 34 mg/kg, 35 mg/kg, 36 mg/kg, 37 mg/kg, 38 mg/kg, 39mg/kg, 40 mg/kg. 41 mg/kg, 42 mg/kg, 43 mg/kg, 44 mg/kg, 45 mg/kg, 46mg/kg, 47 mg/kg, 48 mg/kg, 49 mg/kg, 50 mg/kg, 51 mg/kg, 52 mg/kg, 53mg/kg, 54 mg/kg, 55 mg/kg, 56 mg/kg, 57 mg/kg, 58 mg/kg, 59 mg/kg, 60mg/kg, 61 mg/kg, 62 mg/kg, 63 mg/kg, 64 mg/kg, 65 mg/kg, 66 mg/kg, 67mg/kg, 68 mg/kg, 69 mg/kg, 70 mg/kg, 71 mg/kg, 72 mg/kg, 73 mg/kg, 74mg/kg, 75 mg/kg, 76 mg/kg, 77 mg/kg, 78 mg/kg, 79 mg/kg, or 80 mg/kg.

In some embodiments, the acidified pharmaceutical dosage forms are thosewherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 4.5.

In other embodiments, the acidified pharmaceutical dosage forms arethose wherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 4.2.

In other embodiments, the acidified pharmaceutical dosage forms arethose wherein dissolving an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of water at 25° C., results in asolution having a pH of less than or equal to 4.0.

In some aspects, the acidified pharmaceutical dosage forms are thosereleasing the active ingredient (e.g., the fospropofol or thefospropofol salt) immediately or in modified or extended-release manner.

In some aspects, the acidified pharmaceutical dosage forms are thosewherein dissolution of an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HCl at 37° C., results in atleast 30% (e.g., 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, 98%, or 99% or greater than 99%) of the fospropofol orpharmaceutically acceptable salt thereof (on a fospropofol basis) in thedosage form being released from the dosage form within 60 minutes orless (e.g., within 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10minutes, or within 5 minutes.

In some embodiments, the acidified pharmaceutical dosage forms are thosewherein dissolution of an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HCl at 37° C. results in atleast 30% of the fospropofol or pharmaceutically acceptable salt thereof(on a fospropofol basis) in the dosage form being released from thedosage form within 30 minutes.

In some embodiments, the acidified pharmaceutical dosage forms are thosewherein dissolution of an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HCl at 37° C. results in atleast 50% of the fospropofol or pharmaceutically acceptable salt thereof(on a fospropofol basis) in the dosage form being released from thedosage form within 60 minutes.

In other embodiments, the acidified pharmaceutical dosage forms arethose wherein dissolution of an amount of the dosage form containing atherapeutically effective amount of fospropofol, or a pharmaceuticallyacceptable salt thereof, in 300 mL of 0.1 N HCl at 37° C. results in atleast 90% of the fospropofol or pharmaceutically acceptable salt thereof(on a fospropofol basis) in the dosage form being released from thedosage form within 30 minutes.

In some aspects, the acidified pharmaceutical dosage forms are thosewherein the mole ratio of fospropofol, or a pharmaceutically acceptablesalt thereof, to pharmaceutically acceptable acid is 3:1 or less, suchas, for example, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, 0.5:1,0.55:1, 0.6:1, 0.65:1, 0.7:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, 0.95:1, 1:1,1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1,2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, or 3:1.

The acidified pharmaceutical dosage forms may be tablets, capsules,caplets, softgels, sterile aqueous or organic solutions, reconstitutablepowders, elixirs, liquids, colloidal or other types of suspensions,emulsions, beads, beadlets, granules, microparticles, nanoparticles, andcombinations thereof.

In some embodiments, the acidified pharmaceutical dosage forms is atablet, capsule, or softgel.

In some aspects, the disclosure is directed to methods of administeringfospropofol or a pharmaceutically acceptable salt thereof to a subjectin need thereof, the method comprising orally administering fospropofol,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable acid, to the subject.

In some embodiments, the disclosure is directed to methods ofadministering fospropofol or a pharmaceutically acceptable salt thereofto a subject in need thereof, comprising orally administering to thesubject an acidified pharmaceutical dosage forms.

In other embodiments of the disclosed methods, the subject is orallyco-administered fospropofol (or a pharmaceutically acceptable saltthereof) and a pharmaceutically acceptable acid.

In some embodiments of the disclosed methods, the fospropofol (orpharmaceutically acceptable salt thereof) and the pharmaceuticallyacceptable acid are administered in the same unit dosage form (i.e., thefospropofol or pharmaceutically acceptable salt thereof are present inthe same dosage form together with the pharmaceutically acceptableacid).

In other embodiments, all or a portion of the pharmaceuticallyacceptable acid is administered separately from the dosage formcomprising the fospropofol (or pharmaceutically acceptable saltthereof).

In some embodiments, the methods are for orally administeringfospropofol.

In other embodiments, the methods are for orally administering apharmaceutically acceptable salt of fospropofol.

In other embodiments, the methods are for orally administeringfospropofol disodium.

In some embodiments of the disclosed methods, the pharmaceuticallyacceptable acid used in the methods of the disclosure is1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxethanesulfonic acid, 4-acetamidobenzoic acid, 4-aminosalicyclicacid, acetic acid, aceturic acid, Acid hydrolyzed proteins, AcidModified Starch, Aconitic Acid, adipic acid, alginic acid,a-oxo-glutaric acid, benzenesulfonic acid, benzoic acid, butyric acid,camphor-10-sulfonic acid, camphoric acid, capric acid, caproic acid,caprylic acid, carbonic acid, Cholic acid, cinnamic acid, citric acid,cyclamic acid, D(−)-Lactic acid, Desoxycholic acid, D-glucaric acid,D-glucoheptonic acid, D-glucuronic acid,Di(tert-butyl)naphthalenedisulfonic acid,Di(tert-butyl)naphthalenesulfonic acid, DL-lactic acid, DL-mandelicacid, DL-tartaric acid, tartaric acid, dodecylsulfuric acid, Erythorbicacid (D-isoascorbic acid), ethane-1,2-disulfonic acid, ethanesulfonicacid, formic acid, fumaric acid, galactaric acid, gentisic acid,glutaric acid, glycerophosphoric acid, Glycocholic acid, glycolic acid,hexanedioic acid, hippuric acid, hydrobromic acid, Hydrochloric acid,Iron naphthenate, iron salts, iron salts, isobutyric acid, L(+)-lacticacid, L(+)-potassium acid tartrate, L(+)-tartaric acid, Lactic acid,lactobionic acid, L-ascorbic acid, ascorbic acid, L-aspartic acid,lauric acid, L-glutamic acid, L-Glutamic acid hydrochloride, Linoleicacid, L-Malic acid, L-pyroglutamic acid, L-tartaric acid, maleic acid,malic acid, malonic acid, methanesulfonic acid, monobasic potassiumphosphate, monobasic sodium phosphate, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, naphthenic acids, Niacin (nicotinic acid),nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid,oxalic acid, palmitic acid, pamoic acid, Pectin low acid, Pectinic acid,phosphoric acid, propanoic acid, Propionic acid, p-toluenesulfonic acid,pyruvic acid, saccharin, salicylic acid, sebacic acid, Sodium acidpyrophosphate, Sodium aluminum phosphate, sodium metabisulfite, Sorbicacid, stearic acid, succinic acid, sulfuric acid, tall oil fatty acids,Tannic acid (hydrolyzable gallotannins), Taurocholic acid, thiocyanicacid, Thiodipropionic acid, trifluoroacetic acid, undec-10-enoic acid,orange juice, apple juice, grapefruit juice, or a combination thereof.

In some embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is ascorbic acid. In some embodiments, theascorbic acid is DL-ascorbic acid. In other embodiments, the ascorbicacid is L-ascorbic acid. In other embodiments, the ascorbic acid isD-ascorbic acid.

In other embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is tartaric acid. In some embodiments, thetartaric acid is DL-tartaric acid. In other embodiments, the tartaricacid is L-tartaric acid. In other embodiments, the tartaric acid isD-tartaric acid.

In some embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is citric acid.

In some embodiments, the pharmaceutically acceptable acid used in themethods of the disclosure is malic acid. In some embodiments, the malicacid is DL-malic acid. In other embodiments, the malic acid is L-malicacid. In other embodiments, the malic acid is D-malic acid.

In some methods of the disclosure, the administration of fospropofol (ora pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in a propofol Cmax that is greater than thepropofol Cmax resulting from administering fospropofol, or apharmaceutically acceptable salt thereof, without co-administration ofthe pharmaceutically acceptable acid.

In some embodiments of such methods, the administration of fospropofol(or a pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid comprises administering a pharmaceutical dosage form asdescribed herein, such as, for example, an acidified pharmaceuticaldosage form described herein.

In some embodiments of the methods of the disclosure, the administrationof fospropofol (or a pharmaceutically acceptable salt thereof) and apharmaceutically acceptable acid results in a propofol Cmax that is atleast 1.2 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid,such as for example, at least 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 times greater.

In some embodiments of the methods of the disclosure, the propofol Cmaxis 1.2 times greater than a propofol Cmax resulting from administeringfospropofol, or a pharmaceutically acceptable salt thereof withoutadministration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis at least 1.5 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis at least 2 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis at least 2.5 times greater than a propofol Cmax resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol Cmaxis 3 times greater than a propofol Cmax resulting from administeringfospropofol, or a pharmaceutically acceptable salt thereof, withoutadministration of the pharmaceutically acceptable acid.

In some methods of the disclosure, the administration of fospropofol (ora pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in a propofol AUC that is greater than apropofol AUC resulting from administering fospropofol, or apharmaceutically acceptable salt thereof, without administration of thepharmaceutically acceptable acid.

In some embodiments, the AUC is AUCt.

In other embodiments, the AUC is AUC∞.

In some embodiments of such methods, the administration of fospropofol(or a pharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid comprises administering a pharmaceutical dosage form asdescribed herein, such as, for example, an acidified pharmaceuticaldosage form as described herein.

In some embodiments of the methods of the disclosure, the propofol AUC∞is at least 1.5 times greater than a propofol AUC∞ resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid,such as for example, at least 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, or 4 times greater.

In some embodiments of the methods of the disclosure, the propofol AUC∞is 1.5 times greater than a propofol AUC∞ resulting from administeringfospropofol, or a pharmaceutically acceptable salt thereof, withoutadministration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol AUC∞is at least 1.6 times greater than a propofol AUC∞ resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol AUC∞is at least 2 times greater than a propofol AUC∞ resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol AUC∞is at least 2.5 times greater than a propofol AUC∞ resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some embodiments of the methods of the disclosure, the propofol AUC∞is at least 3 times greater than a propofol AUC∞ resulting fromadministering fospropofol, or a pharmaceutically acceptable saltthereof, without administration of the pharmaceutically acceptable acid.

In some aspects, the methods of the disclosure result in plasmaconcentrations of fospropofol or propofol that exhibit a food effect.The term “food effect,” as used herein, means that the extent and/orrate of drug absorption depends on whether the subject is fed or fastedat the time that the drug is administered.

The term “fed” as used herein, means that means that the subject haseaten food within one hour of less of ingesting the fospropofol or apharmaceutically acceptable salt thereof. For example, following anovernight fast of at least 10 hours, the subject starts a meal 30minutes before administration of the drug product, and eats the mealwithin 30 minutes or less. The fospropofol or a pharmaceuticallyacceptable salt thereof is taken with 240 mL (8 fl. oz.) of water.Additional water is allowed ad lib except for 1 hour before and 1 hourafter drug administration. No food is allowed for at least 4 hours afterthe dose.

In the context of a food effect study, fasted conditions may be asfollows: Following an overnight fast of at least 10 hours, investigatorsshould administer the drug product to study subjects with 240 mL (i.e.,8 fluid ounces) of water. Additional water is permitted ad lib exceptfor the period 1 hour before to 1 hour after administration of the drugproduct. The study subjects should not consume food for at least 4 hoursafter the dose. Subjects should receive standardized meals scheduled atthe same time throughout the study.

The term “fasted” as used herein, means that the subject has not eatenfood within one hour of less of ingesting the fospropofol or apharmaceutically acceptable salt thereof. For example, following anovernight fast of at least 10 hours, fospropofol or a pharmaceuticallyacceptable salt thereof is administered with 240 mL (i.e., 8 fluidounces) of water. Additional water is permitted ad lib except for theperiod 1 hour before to 1 hour after administration of the drug product,the subject does not consume food for at least 4 hours after the dose.

In the context of a food effect study, fed conditions may be as follows:Following an overnight fast of at least 10 hours, the study should startthe recommended meal 30 minutes before administration of the drugproduct. Trial subjects should eat this meal in 30 minutes or less, thestudy subjects should take the drug product with 240 mL (8 fl. oz.) ofwater. Additional water is allowed ad lib except for 1 hour before and 1hour after drug administration. No food is allowed for at least 4 hoursafter the dose.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is about 0.3-1.5, for example, about 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is 0.3 or greater, such as, for example, 0.3, 0.35, 0.4,0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05,1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is about 0.18-1.5, for example, about 0.18, 0.2, 0.25, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is 0.18 or greater, such as, for example, 0.18, 0.2, 0.25,0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9,0.95, 1.0, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, andthe like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed):Cmax (fasted)ratio that is 0.3 or greater, such as, for example, 0.3 or greater, 0.35or greater, 0.4 or greater, 0.45 or greater, 0.5 or greater, 0.55 orgreater, 0.6 or greater, 0.65 or greater, 0.7 or greater, 0.75 orgreater, 0.8 or greater, 0.85 or greater, 0.9 or greater, 0.95 orgreater, 1.0 or greater, 1.05 or greater, 1.1 or greater, 1.15 orgreater, 1.2 or greater, 1.25 or greater, 1.3 or greater, 1.35 orgreater, 1.4 or greater, 1.45 or greater, 1.5 or greater, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed) that is atleast 30% of the corresponding plasma fospropofol Cmax (fasted) such as,for example, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%,150%, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol Cmax (fed) that is atleast 30% of the corresponding plasma fospropofol Cmax (fasted) such as,for example, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 100%, at least 105%, at least 110%, at least 115%, at least 120%,at least 125%, at least 130%, at least 135%, at least 140%, at least145%, at least 150%, and the like.

As used herein, the term “Cmax (fasted)”, refers to the peakconcentration in the plasma a following administration of fospropofol ora pharmaceutically acceptable salt thereof to a subject that is fasted.As used herein, the term “Cmax (fed)”, refers to the peak concentrationin the plasma following administration of fospropofol or apharmaceutically acceptable salt thereof to a subject that is fed. Thepeak concentration of fopropofol in the subject's plasma samples can bedetermined using an appropriate pharmacokinetic model applied to aplasma concentration vs. time profile determined using standardanalytical methods. Appropriate pharmacokinetic models for determiningCmax are known to those of ordinary skill in the art.

In some embodiments of the disclosed methods, the Cmax (fed):Cmax(fasted) ratio is calculated using the arithmetic mean of the individualCmax (fed) values calculated in a population of subjects and thearithmetic mean of the individual Cmax (fasted) values calculated in apopulation of subjects.

In some embodiments, administration of acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol Cmax (fed):Cmax(fasted) ratio that is about 0.3-1.5, for example, about 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5.

In some embodiments, administration of acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol Cmax (fed):Cmax(fasted) ratio that is 0.3 or greater, such as, for example, 0.3, 0.35,0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0,1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, and the like.

In some embodiments, administration of acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol Cmax (fed):Cmax(fasted) ratio that is about 0.18-1.5, for example, about 0.18, 0.2,0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or1.5.

In some embodiments, administration of acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol Cmax (fed):Cmax(fasted) ratio that is 0.18 or greater, such as, for example, 0.18,0.20, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8,0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45,1.5, and the like.

In some embodiments, administration of acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol Cmax (fed):Cmax(fasted) ratio that is 0.3 or greater, such as, for example, 0.3 orgreater, 0.35 or greater, 0.4 or greater, 0.45 or greater, 0.5 orgreater, 0.55 or greater, 0.6 or greater, 0.65 or greater, 0.7 orgreater, 0.75 or greater, 0.8 or greater, 0.85 or greater, 0.9 orgreater, 0.95 or greater, 1.0 or greater, 1.05 or greater, 1.1 orgreater, 1.15 or greater, 1.2 or greater, 1.25 or greater, 1.3 orgreater, 1.35 or greater, 1.4 or greater, 1.45 or greater, 1.5 orgreater, and the like.

In some embodiments, administration of acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol Cmax (fed) that isat least 30% of the corresponding plasma fospropofol Cmax (fasted) suchas, for example, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%,145%, 150%, and the like.

In some embodiments, administration of acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol Cmax (fed) that isat least 30% of the corresponding plasma fospropofol Cmax (fasted) suchas, for example, at least 30%, at least 35%, at least 40%, at least 45%,at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 100%, at least 105%, at least 110%, at least 115%, at least 120%,at least 125%, at least 130%, at least 135%, at least 140%, at least145%, at least 150%, and the like.

In some embodiments of the methods of the disclosure, the ratio of theplasma fospropofol Cmax (fed):Cmax (fasted) resulting fromadministration of fospropofol (or a pharmaceutically acceptable saltthereof) and a pharmaceutically acceptable acid is greater than theratio of plasma fospropofol Cmax (fed):Cmax (fasted) resulting fromadministration of fospropofol (or a pharmaceutically acceptable saltthereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 1.25 times greater, at least 1.5 timesgreater, at least 2 times greater, at least 2.5 times greater, at least3 times greater, at least 3.5 times greater, at least 4 times greater,at least 4.5 times greater, at least 5 times greater, at least 5.5 timesgreater, at least 6 times greater, at least 6.5 times greater, at least7 times greater, at least 7.5 times greater, at least 8 times greater,at least 8.5 times greater, at least 9 times greater, at least 9.5 timesgreater, or at least 10 times greater than the ratio of plasmafospropofol Cmax (fed):Cmax (fasted) resulting from administration offospropofol (or a pharmaceutically acceptable salt thereof) without thepharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 5 times greater or at least 6 times greaterthan the ratio of plasma fospropofol Cmax (fed):Cmax (fasted) resultingfrom administration of a fospropofol (or a pharmaceutically acceptablesalt thereof) composition without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid is atleast 125%, at least 150%, at least 200%, at least 250%, at least 300%,at least 350%, at least 400%, or at least 450%, at least 500%, at least550%, at least 600%, at least 650%, at least 700%, at least 750%, atleast 800%, at least 850%, at least 900%, at least 950%, or at least1000%, of the ratio of plasma fospropofol Cmax (fed):Cmax (fasted)resulting from administering a fospropofol (or a pharmaceuticallyacceptable salt thereof) composition without a pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of the acidified pharmaceuticaldosage forms of the disclosure is at least 1.25 times greater, at least1.5 times greater, at least 2 times greater, at least 2.5 times greater,at least 3 times greater, at least 3.5 times greater, at least 4 timesgreater, at least 4.5 times greater, at least 5 times greater, at least5.5 times greater, at least 6 times greater, at least 6.5 times greater,at least 7 times greater, at least 7.5 times greater, at least 8 timesgreater, at least 8.5 times greater, at least 9 times greater, at least9.5 times greater, or at least 10 times greater than the ratio of plasmafospropofol Cmax (fed):Cmax (fasted) resulting from administration of afospropofol (or a pharmaceutically acceptable salt thereof) compositionwithout the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of the acidified pharmaceuticaldosage forms of the disclosure at least 5 times greater or at least 6times greater than the ratio of plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of a fospropofol (or apharmaceutically acceptable salt thereof) composition without thepharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol Cmax (fed):Cmax(fasted) resulting from administration of the acidified pharmaceuticaldosage forms of the disclosure is at least 125%, at least 150%, at least200%, at least 250%, at least 300%, at least 350%, at least 400%, or atleast 450%, at least 500%, at least 550%, at least 600%, at least 650%,at least 700%, at least 750%, at least 800%, at least 850%, at least900%, at least 950%, or at least 1000%, of the ratio of plasmafospropofol Cmax (fed):Cmax (fasted) resulting from administering afospropofol (or a pharmaceutically acceptable salt thereof) compositionwithout a pharmaceutically acceptable acid.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is about 0.4to 1.0, for example about 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75,0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.4 orgreater, such as, for example, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7,0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, and the like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is about 0.3to 1.0, for example about 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65,0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.3 orgreater, such as, for example, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, andthe like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.4 orgreater, such as, for example, 0.4 or greater, 0.45 or greater, 0.5 orgreater, 0.55 or greater, 0.6 or greater, 0.65 or greater, 0.7 orgreater, 0.75 or greater, 0.8 or greater, 0.85 or greater, 0.9 orgreater, 0.95 or greater, 1.0 or greater, 1.05 or greater, 1.10 orgreater, 1.15 or greater, 1.20 or greater, and the like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin plasma fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.3 orgreater, such as, for example, 0.3 or greater, 0.35 or greater, 0.4 orgreater, 0.45 or greater, 0.5 or greater, 0.55 or greater, 0.6 orgreater, 0.65 or greater, 0.7 or greater, 0.75 or greater, 0.8 orgreater, 0.85 or greater, 0.9 or greater, 0.95 or greater, 1.0 orgreater, 1.05 or greater, 1.10 or greater, 1.15 or greater, 1.20 orgreater, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol AUC∞ (fed) that is atleast 40% of the corresponding plasma fospropofol AUC∞ (fasted) such as,for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, andthe like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma fospropofol AUC∞ (fed) that is atleast 40% of the corresponding plasma fospropofol AUC∞ (fasted) such as,for example, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 100%, at least 105%, atleast 110%, at least 115%, at least 120%, at least 125%, at least 130%,at least 135%, at least 140%, at least 145%, at least 150%, and thelike.

As used herein, the term “AUC∞ (fasted)”, refers to the area under theplasma concentration-time curve from extrapolation of AUC₀ to ∞following administration of fospropofol or a pharmaceutically acceptablesalt thereof to a subject that is fasted. As used herein, the term “AUC∞(fed)”, refers to the area under the plasma concentration-time curvefrom extrapolation of AUC₀ to ∞ following administration of fospropofolor a pharmaceutically acceptable salt thereof to a subject that is fed.Methods for determining concentration-time curves and AUC are known tothose of ordinary skill in the art.

In some embodiments of the disclosed methods, the AUC∞ (fed):AUC∞(fasted) ratio is calculated using the arithmetic mean of the individualAUC∞ (fed) values calculated in a population of subjects and thearithmetic mean of the individual AUC∞ (fasted) values calculated in apopulation of subjects.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fed):AUC∞(fasted) ratio that is about 0.4 to 1.0, for example about 0.4, 0.45,0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fasted):AUC∞(fed) ratio that is 0.4 or greater, such as, for example, 0.4, 0.45,0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10,1.15, 1.20, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fed):AUC∞(fasted) ratio that is about 0.3 to 1.0, for example about 0.3, 0.35,0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and1.0.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fasted):AUC∞(fed) ratio that is 0.3 or greater, such as, for example, 0.3, 0.35,0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0,1.05, 1.10, 1.15, 1.20, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fasted):AUC∞(fed) ratio that is 0.4 or greater, such as, for example, 0.4 orgreater, 0.45 or greater, 0.5 or greater, 0.55 or greater, 0.6 orgreater, 0.65 or greater, 0.7 or greater, 0.75 or greater, 0.8 orgreater, 0.85 or greater, 0.9 or greater, 0.95 or greater, 1.0 orgreater, 1.05 or greater, 1.10 or greater, 1.15 or greater, 1.20 orgreater, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fasted):AUC∞(fed) ratio that is 0.3 or greater, such as, for example, 0.3 orgreater, 0.35 or greater, 0.4 or greater, 0.45 or greater, 0.5 orgreater, 0.55 or greater, 0.6 or greater, 0.65 or greater, 0.7 orgreater, 0.75 or greater, 0.8 or greater, 0.85 or greater, 0.9 orgreater, 0.95 or greater, 1.0 or greater, 1.05 or greater, 1.10 orgreater, 1.15 or greater, 1.20 or greater, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fed) that isat least 40% of the corresponding plasma fospropofol AUC∞ (fasted) suchas, for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%,and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma fospropofol AUC∞ (fed) that isat least 40% of the corresponding plasma fospropofol AUC∞ (fasted) suchas, for example, at least 40%, at least 45%, at least 50%, at least 55%,at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 100%, at least 105%, atleast 110%, at least 115%, at least 120%, at least 125%, at least 130%,at least 135%, at least 140%, at least 145%, at least 150%, and thelike.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid isgreater than the ratio of plasma fospropofol AUC∞ (fed):AUC∞ (fasted)resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid is atleast 1.5 time greater, at least 2 times greater, at least 2.5 timesgreater, at least 3 times greater, at least 3.5 times greater, at least4 times greater, or at least 4.5 times greater than the ratio of plasmafospropofol AUC∞ (fed):AUC∞ (fasted) resulting from administeringfospropofol (or a pharmaceutically acceptable salt thereof) without thepharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid is atleast 2 times greater or at least 2.5 times greater than the ratio ofplasma fospropofol AUC∞ (fed):AUC∞ (fasted) resulting from administeringfospropofol (or a pharmaceutically acceptable salt thereof) without thepharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid is atleast 150%, at least 200%, at least 250%, at least 300%, at least 350%,at least 400%, or at least 450% of the ratio of plasma fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering a fospropofol (or apharmaceutically acceptable salt thereof) composition without apharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering the acidified pharmaceuticaldosage forms of the disclosure is greater than the ratio of plasmafospropofol AUC∞ (fed):AUC∞ (fasted) resulting from administering afospropofol (or a pharmaceutically acceptable salt thereof) compositionwithout a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering the acidified pharmaceuticaldosage forms of the disclosure is at least 1.5 time greater, at least 2times greater, at least 2.5 times greater, at least 3 times greater, atleast 3.5 times greater, at least 4 times greater, or at least 4.5 timesgreater than the ratio of plasma fospropofol AUC∞ (fed):AUC∞ (fasted)resulting from administering a fospropofol (or a pharmaceuticallyacceptable salt thereof) composition without a pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering the acidified pharmaceuticaldosage forms of the disclosure is at least 2 times greater or at least2.5 times greater than the ratio of plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) composition without a pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering the acidified pharmaceuticaldosage forms of the disclosure is at least 150%, at least 200%, at least250%, at least 300%, at least 350%, at least 400%, or at least 450% ofthe ratio of plasma fospropofol AUC∞ (fed):AUC∞ (fasted) resulting fromadministering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that isabout 0.4 to 1.0, for example about 0.4, 0.45, 0.5, 0.55, 0.6, 0.65,0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.4or greater, such as, for example, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7,0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, and the like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that isabout 0.3 to 1.0, for example about 0.3, 0.35, 0.4, 0.45, 0.5, 0.55,0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and 1.0.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.3or greater, such as, for example, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, andthe like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.4or greater, such as, for example, 0.4 or greater, 0.45 or greater, 0.5or greater, 0.55 or greater, 0.6 or greater, 0.65 or greater, 0.7 orgreater, 0.75 or greater, 0.8 or greater, 0.85 or greater, 0.9 orgreater, 0.95 or greater, 1.0 or greater, 1.05 or greater, 1.10 orgreater, 1.15 or greater, 1.20 or greater, and the like.

In some embodiments, administering fospropofol (or a pharmaceuticallyacceptable salt thereof) and a pharmaceutically acceptable acid resultsin a plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) ratio that is 0.3or greater, such as, for example, 0.3 or greater, 0.35 or greater, 0.4or greater, 0.45 or greater, 0.5 or greater, 0.55 or greater, 0.6 orgreater, 0.65 or greater, 0.7 or greater, 0.75 or greater, 0.8 orgreater, 0.85 or greater, 0.9 or greater, 0.95 or greater, 1.0 orgreater, 1.05 or greater, 1.10 or greater, 1.15 or greater, 1.20 orgreater, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma total fospropofol AUC∞ (fed) that isat least 40% of the corresponding plasma total fospropofol AUC∞ (fasted)such as, for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%,150%, and the like.

In some embodiments, administration of fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid results in plasma total fospropofol AUC∞ (fed) that isat least 40% of the corresponding plasma total fospropofol AUC∞ (fasted)such as, for example, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95%, at least 100%, at least105%, at least 110%, at least 115%, at least 120%, at least 125%, atleast 130%, at least 135%, at least 140%, at least 145%, at least 150%,and the like.

As used here, the term “plasma total fospropofol AUC∞ (fasted)”, refersto the sum of the AUC∞ (fasted) for fospropofol and the AUC∞ (fasted)for propofol, following administration of fospropofol or apharmaceutically acceptable salt thereof to a subject that is fasted. Asused here, the term “plasma total fospropofol AUC∞ (fed)”, refers to thesum of the AUC∞ (fed) for fospropofol and the AUC∞ (fed) for propofol,following administration of fospropofol or a pharmaceutically acceptablesalt thereof to a subject that is fed. Methods for determiningconcentration-time curves and AUC are known to those of ordinary skillin the art.

In some embodiments of the disclosed methods, the plasma totalfospropofol AUC∞ (fed):AUC∞ (fasted) ratio is calculated using thearithmetic mean of the individual AUC∞ (fed) values calculated in apopulation of subjects and the arithmetic mean of the individual AUC∞(fasted) values calculated in a population of subjects.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma total fospropofol AUC∞(fasted):AUC∞ (fed) ratio that is about 0.4 to 1.0, for example about0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, and1.0.

In some embodiments, administering the compositions of the disclosureresults in plasma total fospropofol AUC∞ (fasted):AUC∞ (fed) ratio thatis 0.4 or greater, such as, for example, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15, 1.20, andthe like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma total fospropofol AUC∞(fasted):AUC∞ (fed) ratio that is about 0.3 to 1.0, for example about0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9,0.95, and 1.0.

In some embodiments, administering the compositions of the disclosureresults in plasma total fospropofol AUC∞ (fasted):AUC∞ (fed) ratio thatis 0.3 or greater, such as, for example, 0.3, 0.35, 0.4, 0.45, 0.5,0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.10, 1.15,1.20, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma total fospropofol AUC∞(fasted):AUC∞ (fed) ratio that is 0.4 or greater, such as, for example,0.4 or greater, 0.45 or greater, 0.5 or greater, 0.55 or greater, 0.6 orgreater, 0.65 or greater, 0.7 or greater, 0.75 or greater, 0.8 orgreater, 0.85 or greater, 0.9 or greater, 0.95 or greater, 1.0 orgreater, 1.05 or greater, 1.10 or greater, 1.15 or greater, 1.20 orgreater, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma total fospropofol AUC∞(fasted):AUC∞ (fed) ratio that is 0.3 or greater, such as, for example,0.3 or greater, 0.35 or greater, 0.4 or greater, 0.45 or greater, 0.5 orgreater, 0.55 or greater, 0.6 or greater, 0.65 or greater, 0.7 orgreater, 0.75 or greater, 0.8 or greater, 0.85 or greater, 0.9 orgreater, 0.95 or greater, 1.0 or greater, 1.05 or greater, 1.10 orgreater, 1.15 or greater, 1.20 or greater, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma total fospropofol AUC∞ (fed)that is at least 40% of the corresponding plasma total fospropofol AUC∞(fasted) such as, for example, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%,140%, 145%, 150%, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma total fospropofol AUC∞ (fed)that is at least 30% of the corresponding plasma total fospropofol AUC∞(fasted) such as, for example, 30%. 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 130%,135%, 140%, 145%, 150%, and the like.

In some embodiments, administering the acidified pharmaceutical dosageforms of the disclosure results in plasma total fospropofol AUC∞ (fed)that is at least 40% of the corresponding plasma total fospropofol AUC∞(fasted) such as, for example, at least 40%, at least 45%, at least 50%,at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, at least 100%, atleast 105%, at least 110%, at least 115%, at least 120%, at least 125%,at least 130%, at least 135%, at least 140%, at least 145%, at least150%, and the like.

In some embodiments, the ratio of the plasma total fospropofol AUC_(∞)(fed):AUC∞ (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is greater than the ratio of plasma total fospropofolAUC∞ (fed):AUC∞ (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) without the pharmaceuticallyacceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 1.5 time greater, at least 2 times greater,at least 2.5 times greater, at least 3 times greater, at least 3.5 timesgreater, at least 4 times greater, or at least 4.5 times greater thanthe ratio of plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) resultingfrom administering fospropofol (or a pharmaceutically acceptable saltthereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 2 times greater or at least 2.5 timesgreater than the ratio of plasma total fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering fospropofol (or a pharmaceuticallyacceptable salt thereof) without the pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering fospropofol (or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable acid is at least 150%, at least 200%, at least 250%, at least300%, at least 350%, at least 400%, or at least 450% of the ratio ofplasma total fospropofol AUC∞ (fed):AUC∞ (fasted) resulting fromadministering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering the acidifiedpharmaceutical dosage forms of the disclosure is greater than the ratioof plasma total fospropofol AUC∞ (fed):AUC∞ (fasted) resulting fromadministering a fospropofol (or a pharmaceutically acceptable saltthereof) composition without a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering the acidifiedpharmaceutical dosage forms of the disclosure is at least 1.5 timegreater, at least 2 times greater, at least 2.5 times greater, at least3 times greater, at least 3.5 times greater, at least 4 times greater,or at least 4.5 times greater than the ratio of plasma total fospropofolAUC∞ (fed):AUC∞ (fasted) resulting from administering a fospropofol (ora pharmaceutically acceptable salt thereof) composition without apharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering the acidifiedpharmaceutical dosage forms of the disclosure is at least 2 timesgreater or at least 2.5 times greater than the ratio of plasma totalfospropofol AUC∞ (fed):AUC∞ (fasted) resulting from administeringfospropofol (or a pharmaceutically acceptable salt thereof) compositionwithout a pharmaceutically acceptable acid.

In some embodiments, the ratio of the plasma total fospropofol AUC∞(fed):AUC∞ (fasted) resulting from administering the acidifiedpharmaceutical dosage forms of the disclosure is at least 150%, at least200%, at least 250%, at least 300%, at least 350%, at least 400%, or atleast 450% of the ratio of plasma total fospropofol AUC∞ (fed):AUC∞(fasted) resulting from administering a fospropofol (or apharmaceutically acceptable salt thereof) composition without apharmaceutically acceptable acid.

In some embodiments of the disclosed methods, the subject has beenadministered an agent that reduces stomach pH.

In some embodiments of the methods disclosed herein, the subject is ahuman.

In some embodiments of the methods disclosed herein, the subject isexperiencing hypochlorhydria or achlorhydria prior to the administrationof a dosage form as described herein. In some embodiments, the subjectis diagnosed with hypochlorhydria or achlorhydria prior to theadministration. In other embodiments of the methods disclosed herein,the subject is suspected of having hypochlorhydria or achlorhydria priorto the administration.

In some embodiments of the methods disclosed herein, the subject hasbeen administered a proton pump inhibitor (PPI) prior to theadministration of a dosage form as described herein. Exemplary protonpump inhibitors include Omeprazole (Prilosec), Esomeprazole (Nexium),Lansoprazole (Prevacid), Rabeprazole (AcipHex), Pantoprazole (Protonix),Dexlansoprazole (Dexilant), and Zegerid (omeprazole with sodiumbicarbonate).

In some embodiments, the methods described herein are directed totreating a disease or disorder comprising orally administering to asubject a pharmaceutical dosage form described herein.

In other embodiments, the methods described herein are directed totreating a disease or disorder comprising orally administeringfospropofol, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable acid, to a subject.

Fospropofol Salts

The present disclosure also relates to pharmaceutically acceptable saltsof fospropofol, processes for preparation thereof, pharmaceuticalcompositions comprising those salt forms, and methods of treatment usingthose salt forms.

In some embodiments, the methods of treatment disclosed herein areperformed using one or more of the pharmaceutically acceptable salts offospropofol disclosed herein.

In other embodiments, the pharmaceutical compositions disclosed hereincomprise one or more of the pharmaceutically acceptable salts offospropofol disclosed herein.

The fospropofol salts according to the present disclosure may haveadvantageous properties selected from at least one of: chemical orpolymorphic purity, flowability, solubility, dissolution rate,bioavailability, morphology or crystal habit, stability—such as chemicalstability as well as thermal and mechanical stability with respect topolymorphic conversion, stability towards dehydration and/or storagestability, a lower degree of hygroscopicity, low content of residualsolvents and advantageous processing and handling characteristics suchas compressibility, or bulk density.

In some aspects, the present disclosure pertains to pharmaceuticallyacceptable salts of fospropofol. In some embodiments, thepharmaceutically acceptable salts of fospropofol are the potassium,diethylamine, t-butyl amine, ethylene diamine, benzathine, piperazine,ethanolamine, diethanolamine, ammonium, tromethamine, benethamine,histidine, calcium, magnesium, or zinc salts.

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the potassium salt.

In some embodiments, the fospropofol potassium salt has an XRPDsubstantially as shown in FIG. 34 . The XRPD of the potassium salt offospropofol shown in FIG. 34 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table1:

TABLE 1 XRPD Data for Potassium salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.1 99.1 12.0 31.912.3 100.0 13.0 20.5 13.9 13.7 14.9 6.9 15.5 34.6 15.9 7.6 16.2 25.516.4 29.8 17.3 62.3 18.0 21.1 18.7 21.4 18.9 10.3 19.5 28.8 20.0 27.720.9 48.4 21.8 11.0 23.1 66.4 23.7 8.5 24.0 9.4 24.2 12.6 24.8 13.0 25.010.5 25.7 15.5 26.1 9.1 26.3 9.4 27.1 8.8 27.5 15.1 28.1 39.6 28.7 37.129.1 6.7 29.6 8.3 30.0 12.2 30.4 14.8 30.7 16.0 31.4 24.4

In some embodiments of the present disclosure, the potassium salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 1. In other aspects, the potassium salt offospropofol is characterized by an XRPD pattern comprising more than onepeak at one of the angles listed in Table 1 above. In other aspects, thepotassium salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 1 above.In other aspects, the potassium salt of fospropofol is characterized byan XRPD pattern comprising three peaks selected from the angles listedin Table 1 above. In other aspects, the potassium salt of fospropofol ischaracterized by an XRPD pattern comprising four peaks selected from theangles listed in Table 1 above. In other aspects, the potassium salt offospropofol is characterized by an XRPD pattern comprising five peaksselected from the angles listed in Table 1 above. In other aspects, thepotassium salt of fospropofol is characterized by an XRPD patterncomprising six peaks selected from the angles listed in Table 1 above.In other aspects, the potassium salt of fospropofol is characterized byan XRPD pattern comprising seven peaks selected from the angles listedin Table 1 above. In other aspects, the potassium salt of fospropofol ischaracterized by an XRPD pattern comprising eight peaks selected fromthe angles listed in Table 1 above. In other aspects, the potassium saltof fospropofol is characterized by an XRPD pattern comprising nine peaksselected from the angles listed in Table 1 above. In other aspects, thepotassium salt of fospropofol is characterized by an XRPD patterncomprising ten peaks selected from the angles listed in Table 1 above.In other aspects, the potassium salt of fospropofol is characterized byan XRPD pattern comprising more than ten peaks selected from the angleslisted in Table 1 above.

In some embodiments, the potassium salt of fospropofol is characterizedby an XRPD pattern comprising a peak at 12.3, 17.3, and 20.9 degrees±0.2degrees 2-theta. In other embodiments, the potassium salt of fospropofolis characterized by an XRPD pattern comprising peaks at 12.3, 17.3,20.9, and 23.1 degrees±0.2 degrees 2-theta. In other embodiments, thepotassium salt of fospropofol is characterized by an XRPD patterncomprising peaks at 12.3, 17.3, 20.9, 23.1, 28.1, and 28.7 degrees±0.2degree 2-theta. In yet other embodiments, the potassium salt offospropofol is characterized by an XRPD pattern comprising peaks at12.3, 15.5, 16.2, 16.4, 17.3, 18.0, 18.7, 19.5, 20.0, 20.9, 23.1, 28.1,and 28.7 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the potassium salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 12.3, 15.5, 16.2, 16.4, 17.3, 18.0, 18.7, 19.5, 20.0,20.9, 23.1, 28.1, and 28.7 degrees±0.2 degrees 2-theta. In someembodiments of the present disclosure, the potassium salt of fospropofolis characterized by an XRPD pattern comprising peaks at four or more of12.3, 15.5, 16.2, 16.4, 17.3, 18.0, 18.7, 19.5, 20.0, 20.9, 23.1, 28.1,and 28.7 degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the potassium salt of fospropofol is characterized by anXRPD pattern comprising peaks at five or more of 12.3, 15.5, 16.2, 16.4,17.3, 18.0, 18.7, 19.5, 20.0, 20.9, 23.1, 28.1, and 28.7 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, thepotassium salt of fospropofol is characterized by an XRPD patterncomprising peaks at six or more of 12.3, 15.5, 16.2, 16.4, 17.3, 18.0,18.7, 19.5, 20.0, 20.9, 23.1, 28.1, and 28.7 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the potassiumsalt of fospropofol is characterized by an XRPD pattern comprising peaksat seven or more of 12.3, 15.5, 16.2, 16.4, 17.3, 18.0, 18.7, 19.5,20.0, 20.9, 23.1, 28.1, and 28.7 degrees±0.2 degrees 2-theta.

The potassium salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 35 . As FIG. 35 shows, thepotassium salt of fospropofol produced endothermic peaks at 61.8° C.,143.8° C., and 262.2° C. when heated at a rate of 10° C./min. In someembodiments of the present disclosure, the potassium salt of fospropofolis characterized by a DSC thermogram comprising an endothermic peak atabout 62° C. In some embodiments of the present disclosure, thepotassium salt of fospropofol is characterized by a DSC thermogramcomprising an endothermic peak at about 144° C. In some embodiments ofthe present disclosure, the potassium salt of fospropofol ischaracterized by a DSC thermogram comprising an endothermic peak atabout 262° C.

In some embodiments of the present disclosure, the potassium salt offospropofol is characterized by an XRPD pattern comprising peaks at12.3, 17.3, and 20.9 degrees±0.2 degrees 2-theta, and a DSC thermogramcomprising an endothermic peak at about 62° C., 144° C., or 262° C. whenheated at a rate of 10° C./min.

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the diethylamine salt.

In other embodiments, the diethylamine salt of fospropofol (Form II) hasan XRPD substantially as shown in FIG. 36 . The XRPD of the diethylaminesalt of fospropofol shown in FIG. 36 comprises reflection angles(degrees 2-theta±0.2 degrees 2-theta), and relative intensities as shownin Table 2A:

TABLE 2A XRPD Data for Form II Diethylamine salt of Fospropofol AngleRelative (degrees 2-theta ± 0.2 degrees 2-theta) Intensity 5.6 7.7 5.852.5 11.0 100.0 11.5 16.6 11.7 5.1 13.7 3.9 14.6 18.3 17.6 16.9 17.8 4.318.0 3.4 18.7 2.2 19.1 4.5 19.6 4.3 20.9 5.3 22.0 10.7 22.2 5.6 22.5 3.423.0 18.6 23.2 8.4 23.5 10.4 24.1 18.9 24.9 5.7 25.6 8.5 25.9 6.2

In some embodiments of the present disclosure, the diethylamine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 2A. In other aspects, the diethylaminesalt of fospropofol is characterized by an XRPD pattern comprising morethan one peak at one of the angles listed in Table 2A above. In otheraspects, the diethylamine salt of fospropofol is characterized by anXRPD pattern comprising two peaks selected from the angles listed inTable 2A above. In other aspects, the diethylamine salt of fospropofolis characterized by an XRPD pattern comprising three peaks selected fromthe angles listed in Table 2A above. In other aspects, the diethylaminesalt of fospropofol is characterized by an XRPD pattern comprising fourpeaks selected from the angles listed in Table 2A above. In otheraspects, the diethylamine salt of fospropofol is characterized by anXRPD pattern comprising five peaks selected from the angles listed inTable 2A above. In other aspects, the diethylamine salt of fospropofolis characterized by an XRPD pattern comprising six peaks selected fromthe angles listed in Table 2A above. In other aspects, the diethylaminesalt of fospropofol is characterized by an XRPD pattern comprising sevenpeaks selected from the angles listed in Table 2A above. In otheraspects, the diethylamine salt of fospropofol is characterized by anXRPD pattern comprising eight peaks selected from the angles listed inTable 2A above. In other aspects, the diethylamine salt of fospropofolis characterized by an XRPD pattern comprising nine peaks selected fromthe angles listed in Table 2A above. In other aspects, the diethylaminesalt of fospropofol is characterized by an XRPD pattern comprising tenpeaks selected from the angles listed in Table 2A above. In otheraspects, the diethylamine salt of fospropofol is characterized by anXRPD pattern comprising more than ten peaks selected from the angleslisted in Table 2A above.

In some embodiments, the diethylamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peaks at 5.8 and 11.0degrees±0.2 degrees 2-theta. In other embodiments, the diethylamine saltof fospropofol is characterized by an XRPD pattern comprising peaks at5.8, 11.0, and 11.5 degrees±0.2 degrees 2-theta. In other embodiments,the diethylamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 5.8, 11.0, 11.5, 14.6, and 17.6 degrees±0.2 degree2-theta. In yet other embodiments, the diethylamine salt of fospropofolis characterized by an XRPD pattern comprising peaks at 5.8, 11.0, 11.5,14.6, 17.6, 22.0, 23.0, and 24.1 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the diethylamine salt offospropofol is characterized by an XRPD pattern comprising peaks at twoor more of 5.8, 11.0, 11.5, 14.6, 17.6, 22.0, 23.0, and 24.1 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, thediethylamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at three or more of 5.8, 11.0, 11.5, 14.6, 17.6, 22.0,23.0, and 24.1 degrees±0.2 degrees 2-theta. In some embodiments of thepresent disclosure, the diethylamine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at four or more of5.8, 11.0, 11.5, 14.6, 17.6, 22.0, 23.0, and 24.1 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the diethylaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat five or more of 5.8, 11.0, 11.5, 14.6, 17.6, 22.0, 23.0, and 24.1degrees±0.2 degrees 2-theta.

In some embodiments, the diethylamine salt of fospropofol (Form I) hasan XRPD substantially as shown in FIG. 37 . The XRPD of the diethylaminesalt of fospropofol shown in FIG. 37 comprises reflection angles(degrees 2-theta±0.2 degrees 2-theta), and relative intensities as shownin Table 2:

TABLE 2 XRPD Data for Form I Diethylamine salt of Fospropofol AngleRelative (degrees 2-theta ± 0.2 degrees 2-theta) Intensity 5.9 6.2 7.39.2 7.4 11.4 8.2 15.7 9.8 7.1 10.6 10.0 10.7 47.1 10.9 100.0 11.4 16.312.2 8.5 12.3 10.9 13.1 9.1 14.6 8.2 14.9 6.5 15.6 6.5 16.3 5.2 16.6 6.217.5 6.8 18.0 9.9 18.6 5.7 19.6 5.4 20.1 5.4 21.7 6.8 23.0 8.5 23.2 9.223.6 8.3 24.2 14.5 25.9 11.6 27.5 12.0

In some embodiments of the present disclosure, the diethylamine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 2. In other aspects, the diethylamine saltof fospropofol is characterized by an XRPD pattern comprising more thanone peak at one of the angles listed in Table 2 above. In other aspects,the diethylamine salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 2 above.In other aspects, the diethylamine salt of fospropofol is characterizedby an XRPD pattern comprising three peaks selected from the angleslisted in Table 2 above. In other aspects, the diethylamine salt offospropofol is characterized by an XRPD pattern comprising four peaksselected from the angles listed in Table 2 above. In other aspects, thediethylamine salt of fospropofol is characterized by an XRPD patterncomprising five peaks selected from the angles listed in Table 2 above.In other aspects, the diethylamine salt of fospropofol is characterizedby an XRPD pattern comprising six peaks selected from the angles listedin Table 2 above. In other aspects, the diethylamine salt of fospropofolis characterized by an XRPD pattern comprising seven peaks selected fromthe angles listed in Table 2 above. In other aspects, the diethylaminesalt of fospropofol is characterized by an XRPD pattern comprising eightpeaks selected from the angles listed in Table 2 above. In otheraspects, the diethylamine salt of fospropofol is characterized by anXRPD pattern comprising nine peaks selected from the angles listed inTable 2 above. In other aspects, the diethylamine salt of fospropofol ischaracterized by an XRPD pattern comprising ten peaks selected from theangles listed in Table 2 above. In other aspects, the diethylamine saltof fospropofol is characterized by an XRPD pattern comprising more thanten peaks selected from the angles listed in Table 2 above.

In some embodiments, the diethylamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peak at 10.9 and 11.4degrees±0.2 degrees 2-theta. In other embodiments, the diethylamine saltof fospropofol is characterized by an XRPD pattern comprising peaks at10.9, 11.4, and 14.6 degrees±0.2 degrees 2-theta. In other embodiments,the diethylamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 10.9, 11.4, 14.6, and 24.2 degrees±0.2 degree2-theta. In yet other embodiments, the diethylamine salt of fospropofolis characterized by an XRPD pattern comprising peaks at 10.9, 11.4,14.6, 24.2, 25.9, and 27.5 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the diethylamine salt offospropofol is characterized by an XRPD pattern comprising peaks at twoor more of 10.9, 11.4, 14.6, 24.2, 25.9, and 27.5 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the diethylaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat three or more of 10.9, 11.4, 14.6, 24.2, 25.9, and 27.5 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, thediethylamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at four or more of 10.9, 11.4, 14.6, 24.2, 25.9, and27.5 degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the diethylamine salt of fospropofol is characterized by anXRPD pattern comprising peaks at five or more of 10.9, 11.4, 14.6, 24.2,25.9, and 27.5 degrees±0.2 degrees 2-theta.

The Form I diethylamine salt of fospropofol can be characterized by aDSC thermogram substantially as shown in FIG. 38 . As FIG. 38 shows, thediethylamine salt of fospropofol produced endothermic peaks at about 98°C. when heated at a rate of 10° C./min. In some embodiments of thepresent disclosure, the diethylamine salt of fospropofol ischaracterized by a DSC thermogram comprising an endothermic peak atabout 98° C.

In some embodiments of the present disclosure, the diethylamine salt offospropofol is characterized by an XRPD pattern comprising peaks at oneor more of 10.9, 11.4, 14.6, 24.2, 25.9, and 27.5 degrees±0.2 degrees2-theta, and a DSC thermogram comprising an endothermic peak at about98° C. when heated at a rate of 10° C./min.

The Form I diethylamine salt of fospropofol can be characterized by anNMR spectrum substantially as shown in FIG. 39 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the t-butylamine salt.

In some embodiments, the t-butylamine salt of fospropofol has an XRPDsubstantially as shown in FIG. 40 . The XRPD of the t-butylamine salt offospropofol shown in FIG. 40 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table3:

TABLE 3 XRPD Data for t-butylamine salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 6.3 39.4 8.5 12.2 9.044.6 9.6 19.1 9.7 36.3 10.7 8.5 12.2 100.0 12.5 23.0 17.1 23.8 18.5 20.719.5 62.3 19.7 15.9 20.8 10.5 21.3 13.1 21.7 14.0 22.8 19.6 23.9 25.524.4 7.4 25.2 7.7 26.4 17.7 28.3 11.4 28.8 22.8 29.5 7.6

In some embodiments of the present disclosure, the t-butylamine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 3. In other aspects, the t-butylamine saltof fospropofol is characterized by an XRPD pattern comprising more thanone peak at one of the angles listed in Table 3 above. In other aspects,the t-butylamine salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 3 above.In other aspects, the t-butylamine salt of fospropofol is characterizedby an XRPD pattern comprising three peaks selected from the angleslisted in Table 3 above. In other aspects, the t-butylamine salt offospropofol is characterized by an XRPD pattern comprising four peaksselected from the angles listed in Table 3 above. In other aspects, thet-butylamine salt of fospropofol is characterized by an XRPD patterncomprising five peaks selected from the angles listed in Table 3 above.In other aspects, the t-butylamine salt of fospropofol is characterizedby an XRPD pattern comprising six peaks selected from the angles listedin Table 3 above. In other aspects, the t-butylamine salt of fospropofolis characterized by an XRPD pattern comprising seven peaks selected fromthe angles listed in Table 3 above. In other aspects, the t-butylaminesalt of fospropofol is characterized by an XRPD pattern comprising eightpeaks selected from the angles listed in Table 3 above. In otheraspects, the t-butylamine salt of fospropofol is characterized by anXRPD pattern comprising nine peaks selected from the angles listed inTable 3 above. In other aspects, the t-butylamine salt of fospropofol ischaracterized by an XRPD pattern comprising ten peaks selected from theangles listed in Table 3 above. In other aspects, the t-butylamine saltof fospropofol is characterized by an XRPD pattern comprising more thanten peaks selected from the angles listed in Table 3 above.

In some embodiments, the t-butylamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peak at 12.2 degrees±0.2degrees 2-theta. In other embodiments, the t-butylamine salt offospropofol is characterized by an XRPD pattern comprising peaks at 9.0,9.6, and 12.2 degrees t 0.2 degrees 2-theta. In other embodiments, thet-butylamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 9.0, 9.6, 12.2, 17.1, and 19.5 degrees±0.2 degree2-theta. In yet other embodiments, the t-butylamine salt of fospropofolis characterized by an XRPD pattern comprising peaks at 9.0, 9.6, 12.2,17.1, 19.5, 21.3, 21.7, 23.9, 26.4, 28.3, and 28.8 degrees±0.2 degree2-theta.

In some embodiments of the present disclosure, the t-butylamine salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 9.0, 9.6, 12.2, 17.1, 19.5, 21.3, 21.7, 23.9, 26.4,28.3, and 28.8 degrees±0.2 degrees 2-theta. In some embodiments of thepresent disclosure, the t-butylamine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at four or more of9.0, 9.6, 12.2, 17.1, 19.5, 21.3, 21.7, 23.9, 26.4, 28.3, and 28.8degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the t-butylamine salt of fospropofol is characterized by anXRPD pattern comprising peaks at five or more of 9.0, 9.6, 12.2, 17.1,19.5, 21.3, 21.7, 23.9, 26.4, 28.3, and 28.8 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the t-butylaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat six or more of 9.0, 9.6, 12.2, 17.1, 19.5, 21.3, 21.7, 23.9, 26.4,28.3, and 28.8 degrees±0.2 degrees 2-theta. In some embodiments of thepresent disclosure, the t-butylamine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at seven or more of9.0, 9.6, 12.2, 17.1, 19.5, 21.3, 21.7, 23.9, 26.4, 28.3, and 28.8degrees±0.2 degrees 2-theta.

The t-butylamine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 41 . As FIG. 41 shows, thet-butylamine salt of fospropofol produced endothermic peaks at about58.2° C. and 195.2° C. when heated at a rate of 10° C./min. In someembodiments of the present disclosure, the t-butylamine salt offospropofol is characterized by a DSC thermogram comprising anendothermic peak at about 58° C., or at about 195° C.

In some embodiments of the present disclosure, the t-butylamine salt offospropofol is characterized by an XRPD pattern comprising peaks at oneor more of 9.0, 9.6, 12.2, 17.1, 19.5, 21.3, 21.7, 23.9, 26.4, 28.3, and28.8 degrees±0.2 degrees 2-theta, and a DSC thermogram comprising anendothermic peak at about 58° C., or at about 195° C. when heated at arate of 10° C./min.

The t-butylamine salt of fospropofol can be characterized by an NMRspectrum substantially as shown in FIG. 42 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the ethylene diamine salt.

In some embodiments, the ethylene diamine salt of fospropofol has anXRPD substantially as shown in FIG. 43 . The XRPD of the ethylenediamine salt of fospropofol shown in FIG. 43 comprises reflection angles(degrees 2-theta±0.2 degrees 2-theta), and relative intensities as shownin Table 4:

TABLE 4 XRPD Data for ethylene diamine salt of Fospropofol AngleRelative (degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.8 100.010.5 5.4 11.9 17.4 12.6 63.1 13.7 18.2 14.3 6.6 14.5 7.4 15.1 45.8 17.834.0 18.2 11.9 18.4 17.1 18.6 17.3 19.4 16.8 19.5 12.0 20.1 24.4 20.38.3 23.4 15.1 23.6 22.5 23.9 29.5 24.3 10.2 24.7 12.8 25.0 10.6 25.6 4.925.9 10.6 26.4 4.9 27.0 8.0 27.4 5.6 28.0 5.2 28.5 6.5 29.6 7.4 31.611.6

In some embodiments of the present disclosure, the ethylene diamine saltof fospropofol is characterized by an XRPD pattern comprising a peak atone of the angles listed in Table 4. In other aspects, the ethylenediamine salt of fospropofol is characterized by an XRPD patterncomprising more than one peak at one of the angles listed in Table 4above. In other aspects, the ethylene diamine salt of fospropofol ischaracterized by an XRPD pattern comprising two peaks selected from theangles listed in Table 4 above. In other aspects, the ethylene diaminesalt of fospropofol is characterized by an XRPD pattern comprising threepeaks selected from the angles listed in Table 4 above. In otheraspects, the ethylene diamine salt of fospropofol is characterized by anXRPD pattern comprising four peaks selected from the angles listed inTable 4 above. In other aspects, the ethylene diamine salt offospropofol is characterized by an XRPD pattern comprising five peaksselected from the angles listed in Table 4 above. In other aspects, theethylene diamine salt of fospropofol is characterized by an XRPD patterncomprising six peaks selected from the angles listed in Table 4 above.In other aspects, the ethylene diamine salt of fospropofol ischaracterized by an XRPD pattern comprising seven peaks selected fromthe angles listed in Table 4 above. In other aspects, the ethylenediamine salt of fospropofol is characterized by an XRPD patterncomprising eight peaks selected from the angles listed in Table 4 above.In other aspects, the ethylene diamine salt of fospropofol ischaracterized by an XRPD pattern comprising nine peaks selected from theangles listed in Table 4 above. In other aspects, the ethylene diaminesalt of fospropofol is characterized by an XRPD pattern comprising tenpeaks selected from the angles listed in Table 4 above. In otheraspects, the ethylene diamine salt of fospropofol is characterized by anXRPD pattern comprising more than ten peaks selected from the angleslisted in Table 4 above.

In some embodiments, the ethylene diamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peak at 12.6 degrees±0.2degrees 2-theta. In other embodiments, the ethylene diamine salt offospropofol is characterized by an XRPD pattern comprising peaks at11.9, 12.6, and 13.7 degrees±0.2 degrees 2-theta. In other embodiments,the ethylene diamine salt of fospropofol is characterized by an XRPDpattern comprising peaks at 11.9, 12.6, 13.7, 15.1, 17.8, and 20.1degrees±0.2 degree 2-theta. In yet other embodiments, the ethylenediamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 11.9, 12.6, 13.7, 15.1, 17.8, 20.1, 23.6, and 23.9degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the ethylene diamine saltof fospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 11.9, 12.6, 13.7, 15.1, 17.8, 20.1, 23.6, and 23.9degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the ethylene diamine salt of fospropofol is characterized byan XRPD pattern comprising peaks at four or more of 11.9, 12.6, 13.7,15.1, 17.8, 20.1, 23.6, and 23.9 degrees±0.2 degrees 2-theta. In someembodiments of the present disclosure, the ethylene diamine salt offospropofol is characterized by an XRPD pattern comprising peaks at fiveor more of 11.9, 12.6, 13.7, 15.1, 17.8, 20.1, 23.6, and 23.9degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the ethylene diamine salt of fospropofol is characterized byan XRPD pattern comprising peaks at six or more of 11.9, 12.6, 13.7,15.1, 17.8, 20.1, 23.6, and 23.9 degrees±0.2 degrees 2-theta. In someembodiments of the present disclosure, the ethylene diamine salt offospropofol is characterized by an XRPD pattern comprising peaks atseven or more of 11.9, 12.6, 13.7, 15.1, 17.8, 20.1, 23.6, and 23.9degrees±0.2 degrees 2-theta.

The ethylene diamine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 44 . As FIG. 44 shows, theethylene diamine salt of fospropofol produced endothermic peaks at about88.6° C. and 191.6° C. when heated at a rate of 10° C./min. In someembodiments of the present disclosure, the ethylene diamine salt offospropofol is characterized by a DSC thermogram comprising anendothermic peak at about 89° C., or at about 192° C.

In some embodiments of the present disclosure, the ethylene diamine saltof fospropofol is characterized by an XRPD pattern comprising peaks atone or more of 11.9, 12.6, 13.7, 15.1, 17.8, 20.1, 23.6, and 23.9degrees±0.2 degrees 2-theta, and a DSC thermogram comprising anendothermic peak at about 89° C., or at about 192° C., when heated at arate of 10° C./min.

The ethylene diamine salt of fospropofol can be characterized by an NMRspectrum substantially as shown in FIG. 45 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the benzathine (i.e., N¹,N²-dibenzylethane-1,2-diamine) salt.

The benzathine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 46 . As FIG. 46 shows, thebenzathine salt of fospropofol produced endothermic peak at about 111.3°C. when heated at a rate of 10° C./min. In some embodiments of thepresent disclosure, the benzathine salt of fospropofol is characterizedby a DSC thermogram comprising an endothermic peak at about 111° C.

The benzathine salt of fospropofol can be characterized by an NMRspectrum substantially as shown in FIG. 47 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the piperazine salt.

In some embodiments, the piperazine salt of fospropofol has an XRPDsubstantially as shown in FIG. 48 . The XRPD of the piperazine salt offospropofol shown in FIG. 48 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table6:

TABLE 6 XRPD Data for piperazine salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 3.7 23.9 4.9 100.0 7.417.3 9.2 36.8 9.9 12.2 10.6 8.5 10.9 30.4 13.0 16.3 14.4 9.6 14.9 9.215.2 8.3 16.3 16.2 16.9 11.6 17.4 30.0 19.1 15.4 19.3 12.2 20.0 18.220.4 22.5 21.3 24.3 21.9 20.3 23.2 18.0 24.3 14.3 24.8 9.1 25.8 8.8 26.97.6

In some embodiments of the present disclosure, the piperazine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 6. In other aspects, the piperazine saltof fospropofol is characterized by an XRPD pattern comprising more thanone peak at one of the angles listed in Table 6 above. In other aspects,the piperazine salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 6 above.In other aspects, the piperazine salt of fospropofol is characterized byan XRPD pattern comprising three peaks selected from the angles listedin Table 6 above. In other aspects, the piperazine salt of fospropofolis characterized by an XRPD pattern comprising four peaks selected fromthe angles listed in Table 6 above. In other aspects, the piperazinesalt of fospropofol is characterized by an XRPD pattern comprising fivepeaks selected from the angles listed in Table 6 above. In otheraspects, the piperazine salt of fospropofol is characterized by an XRPDpattern comprising six peaks selected from the angles listed in Table 6above. In other aspects, the piperazine salt of fospropofol ischaracterized by an XRPD pattern comprising seven peaks selected fromthe angles listed in Table 6 above. In other aspects, the piperazinesalt of fospropofol is characterized by an XRPD pattern comprising eightpeaks selected from the angles listed in Table 6 above. In otheraspects, the piperazine salt of fospropofol is characterized by an XRPDpattern comprising nine peaks selected from the angles listed in Table 6above. In other aspects, the piperazine salt of fospropofol ischaracterized by an XRPD pattern comprising ten peaks selected from theangles listed in Table 6 above. In other aspects, the piperazine salt offospropofol is characterized by an XRPD pattern comprising more than tenpeaks selected from the angles listed in Table 6 above.

In some embodiments, the piperazine salt of fospropofol is characterizedby an XRPD pattern comprising a peak at 4.9, 9.2, and 10.9 degrees±0.2degrees 2-theta. In other embodiments, the piperazine salt offospropofol is characterized by an XRPD pattern comprising peaks at 4.9,9.2, 10.9, 13.0, 16.3, and 17.4 degrees±0.2 degrees 2-theta. In otherembodiments, the piperazine salt of fospropofol is characterized by anXRPD pattern comprising peaks at 20.0, 20.4, 21.3, 21.9, 23.2, and 24.3degrees±0.2 degree 2-theta. In yet other embodiments, the piperazinesalt of fospropofol is characterized by an XRPD pattern comprising peaksat 4.9, 9.2, 10.9, 13.0, 16.3, 17.4, 20.0, 20.4, 21.3, 21.9, 23.2, and24.3 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the piperazine salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 4.9, 9.2, 10.9, 13.0, 16.3, 17.4, 20.0, 20.4, 21.3,21.9, 23.2, and 24.3 degrees±0.2 degrees 2-theta. In some embodiments ofthe present disclosure, the piperazine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at four or more of4.9, 9.2, 10.9, 13.0, 16.3, 17.4, 20.0, 20.4, 21.3, 21.9, 23.2, and 24.3degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the piperazine salt of fospropofol is characterized by anXRPD pattern comprising peaks at five or more of 4.9, 9.2, 10.9, 13.0,16.3, 17.4, 20.0, 20.4, 21.3, 21.9, 23.2, and 24.3 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the piperazinesalt of fospropofol is characterized by an XRPD pattern comprising peaksat six or more of 4.9, 9.2, 10.9, 13.0, 16.3, 17.4, 20.0, 20.4, 21.3,21.9, 23.2, and 24.3 degrees±0.2 degrees 2-theta. In some embodiments ofthe present disclosure, the piperazine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at seven or more of4.9, 9.2, 10.9, 13.0, 16.3, 17.4, 20.0, 20.4, 21.3, 21.9, 23.2, and 24.3degrees±0.2 degrees 2-theta.

The piperazine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 49 . As FIG. 49 shows, thepiperazine salt of fospropofol produced endothermic peak at 96.3° C.,150.9° C., and 195.2° C. when heated at a rate of 10° C./min. In someembodiments of the present disclosure, the piperazine salt offospropofol is characterized by a DSC thermogram comprising anendothermic peak at about 96° C., 151° C., or 195° C. when heated at arate of 10° C./min.

In some embodiments of the present disclosure, the piperazine salt offospropofol is characterized by an XRPD pattern comprising peaks at oneor more of 4.9, 9.2, 10.9, 13.0, 16.3, 17.4, 20.0, 20.4, 21.3, 21.9,23.2, and 24.3 degrees±0.2 degrees 2-theta, and a DSC thermogramcomprising an endothermic peak at about 96° C., 151° C., or 195° C. whenheated at a rate of 10° C./min.

The piperazine salt of fospropofol can be characterized by an NMRspectrum substantially as shown in FIG. 50 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the ethanolamine salt.

In some embodiments, the ethanolamine salt of fospropofol (Form II) hasan XRPD substantially as shown in FIG. 51 . The XRPD of the Form IIethanolamine salt of fospropofol shown in FIG. 51 comprises reflectionangles (degrees 2-theta±0.2 degrees 2-theta), and relative intensitiesas shown in Table 7A:

TABLE 7A XRPD Data for Form II ethanolamine salt of Fospropofol AngleRelative (degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.8 100.010.0 19.0 12.1 11.9 12.5 35.5 14.2 24.1 18.5 13.1 19.6 10.6 20.6 11.621.9 39.5 25.1 35.6

In some embodiments of the present disclosure, the ethanolamine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 7A. In other aspects, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising morethan one peak at one of the angles listed in Table 7A above. In otheraspects, the ethanolamine salt of fospropofol is characterized by anXRPD pattern comprising two peaks selected from the angles listed inTable 7A above. In other aspects, the ethanolamine salt of fospropofolis characterized by an XRPD pattern comprising three peaks selected fromthe angles listed in Table 7A above. In other aspects, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising fourpeaks selected from the angles listed in Table 7A above. In otheraspects, the ethanolamine salt of fospropofol is characterized by anXRPD pattern comprising five peaks selected from the angles listed inTable 7A above. In other aspects, the ethanolamine salt of fospropofolis characterized by an XRPD pattern comprising six peaks selected fromthe angles listed in Table 7A above. In other aspects, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising sevenpeaks selected from the angles listed in Table 7A above. In otheraspects, the ethanolamine salt of fospropofol is characterized by anXRPD pattern comprising eight peaks selected from the angles listed inTable 7A above. In other aspects, the ethanolamine salt of fospropofolis characterized by an XRPD pattern comprising nine peaks selected fromthe angles listed in Table 7A above. In other aspects, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising tenpeaks selected from the angles listed in Table 7A above. In otheraspects, the ethanolamine salt of fospropofol is characterized by anXRPD pattern comprising more than ten peaks selected from the angleslisted in Table 7A above.

In some embodiments, the ethanolamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peaks at 12.5, and 14.2degrees degrees±0.2 degrees 2-theta. In other embodiments, theethanolamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 12.5, 14.2, and 21.9 degrees±0.2 degrees 2-theta. Inother embodiments, the ethanolamine salt of fospropofol is characterizedby an XRPD pattern comprising peaks at 12.5, 14.2, 21.9, and 25.1degrees±0.2 degree 2-theta. In yet other embodiments, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat 4.8, 12.5, 14.2, 21.9, and 25.1 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the ethanolamine salt offospropofol is characterized by an XRPD pattern comprising peaks at twoor more of 4.8, 12.5, 14.2, 21.9, and 25.1 degrees degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat three or more of 4.8, 12.5, 14.2, 21.9, and 25.1 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat four or more of 4.8, 12.5, 14.2, 21.9, and 25.1 degrees±0.2 degrees2-theta.

In other embodiments, the ethanolamine salt of fospropofol (Form I) hasan XRPD substantially as shown in FIG. 52 . The XRPD of the Form Iethanolamine salt of fospropofol shown in FIG. 52 comprises reflectionangles (degrees 2-theta±0.2 degrees 2-theta), and relative intensitiesas shown in Table 7:

TABLE 7 XRPD Data for Form I ethanolamine salt of Fospropofol AngleRelative (degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.8 100.010.0 44.4 11.4 4.9 14.8 9.0 15.3 20.1 15.5 13.0 15.9 19.0 17.0 16.0 17.112.7 17.6 12.5 18.2 16.5 18.5 35.5 19.6 19.3 20.9 14.2 21.4 8.0 21.712.2 22.5 6.0 22.9 6.2 23.3 12.3 24.0 7.7 24.6 5.7 24.9 9.6

In some embodiments of the present disclosure, the ethanolamine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 7. In other aspects, the ethanolamine saltof fospropofol is characterized by an XRPD pattern comprising more thanone peak at one of the angles listed in Table 7 above. In other aspects,the ethanolamine salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 7 above.In other aspects, the ethanolamine salt of fospropofol is characterizedby an XRPD pattern comprising three peaks selected from the angleslisted in Table 7 above. In other aspects, the ethanolamine salt offospropofol is characterized by an XRPD pattern comprising four peaksselected from the angles listed in Table 7 above. In other aspects, theethanolamine salt of fospropofol is characterized by an XRPD patterncomprising five peaks selected from the angles listed in Table 7 above.In other aspects, the ethanolamine salt of fospropofol is characterizedby an XRPD pattern comprising six peaks selected from the angles listedin Table 7 above. In other aspects, the ethanolamine salt of fospropofolis characterized by an XRPD pattern comprising seven peaks selected fromthe angles listed in Table 7 above. In other aspects, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising eightpeaks selected from the angles listed in Table 7 above. In otheraspects, the ethanolamine salt of fospropofol is characterized by anXRPD pattern comprising nine peaks selected from the angles listed inTable 7 above. In other aspects, the ethanolamine salt of fospropofol ischaracterized by an XRPD pattern comprising ten peaks selected from theangles listed in Table 7 above. In other aspects, the ethanolamine saltof fospropofol is characterized by an XRPD pattern comprising more thanten peaks selected from the angles listed in Table 7 above.

In some embodiments, the ethanolamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peak at 10.0 degrees±0.2degrees 2-theta. In other embodiments, the ethanolamine salt offospropofol is characterized by an XRPD pattern comprising peaks at10.0, 18.5, 19.6, and 20.9 degrees±0.2 degrees 2-theta. In otherembodiments, the ethanolamine salt of fospropofol is characterized by anXRPD pattern comprising peaks at 10.0, 17.0, 18.5, 19.6, and 20.9degrees±0.2 degree 2-theta. In yet other embodiments, the ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat 10.0, 15.3, 15.9, 17.0, 18.5, 19.6, and 20.9 degrees±0.2 degree2-theta.

In some embodiments of the present disclosure, the ethanolamine salt offospropofol is characterized by an XRPD pattern comprising peaks at twoor more of 10.0, 15.3, 15.9, 17.0, 18.5, 19.6, and 20.9 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, theethanolamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at three or more of 10.0, 15.3, 15.9, 17.0, 18.5, 19.6,and 20.9 degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the ethanolamine salt of fospropofol is characterized by anXRPD pattern comprising peaks at four or more of 10.0, 15.3, 15.9, 17.0,18.5, 19.6, and 20.9 degrees±0.2 degrees 2-theta. In some embodiments ofthe present disclosure, the ethanolamine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at five or more of10.0, 15.3, 15.9, 17.0, 18.5, 19.6, and 20.9 degrees 0.2 degrees2-theta.

The Form I ethanolamine salt of fospropofol can be characterized by aDSC thermogram substantially as shown in FIG. 53 . As FIG. 53 shows, theethanolamine salt of fospropofol produced endothermic peak at 95.5° C.and 174.2° C. when heated at a rate of 10° C./min. In some embodimentsof the present disclosure, the ethanolamine salt of fospropofol ischaracterized by a DSC thermogram comprising an endothermic peak atabout 96° C., or about 174° C. when heated at a rate of 10° C./min.

In some embodiments of the present disclosure, the Form I ethanolaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat one or more of 10.0, 15.3, 15.9, 17.0, 18.5, 19.6, and 20.9degrees±0.2 degrees 2-theta, and a DSC thermogram comprising anendothermic peak at about 96° C., or about 174° C. when heated at a rateof 10° C./min.

The Form I ethanolamine salt of fospropofol can be characterized by anNMR spectrum substantially as shown in FIG. 54 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the diethanolamine salt.

The diethanolamine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 55 . As FIG. 55 shows, thediethanolamine salt of fospropofol produced endothermic peak at 57.2° C.when heated at a rate of 10° C./min. In some embodiments of the presentdisclosure, the diethanolamine salt of fospropofol is characterized by aDSC thermogram comprising an endothermic peak at about 57° C. whenheated at a rate of 10° C./min.

The diethanolamine salt of fospropofol can be characterized by an NMRspectrum substantially as shown in FIG. 56 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the ammonium salt.

In some embodiments, the ammonium salt of fospropofol has an XRPDsubstantially as shown in FIG. 57 . The XRPD of the ammonium salt offospropofol shown in FIG. 57 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table9:

TABLE 9 XRPD Data for ammonium salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.3 100.0 8.6 14.711.2 14.2 12.2 43.7 14.2 28.7 14.5 14.0 15.9 18.1 16.9 9.0 17.1 16.817.5 12.8 18.1 98.5 18.5 25.9 18.9 14.2 19.2 18.8 19.6 10.5 20.5 10.221.1 16.5 21.8 14.0 22.6 8.3 23.2 11.0 24.1 8.5 24.8 11.3 25.8 21.6 26.610.3 26.9 9.0

In some embodiments of the present disclosure, the ammonium salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 9. In other aspects, the ammonium salt offospropofol is characterized by an XRPD pattern comprising more than onepeak at one of the angles listed in Table 9 above. In other aspects, theammonium salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 9 above.In other aspects, the ammonium salt of fospropofol is characterized byan XRPD pattern comprising three peaks selected from the angles listedin Table 9 above. In other aspects, the ammonium salt of fospropofol ischaracterized by an XRPD pattern comprising four peaks selected from theangles listed in Table 9 above. In other aspects, the ammonium salt offospropofol is characterized by an XRPD pattern comprising five peaksselected from the angles listed in Table 9 above. In other aspects, theammonium salt of fospropofol is characterized by an XRPD patterncomprising six peaks selected from the angles listed in Table 9 above.In other aspects, the ammonium salt of fospropofol is characterized byan XRPD pattern comprising seven peaks selected from the angles listedin Table 9 above. In other aspects, the ammonium salt of fospropofol ischaracterized by an XRPD pattern comprising eight peaks selected fromthe angles listed in Table 9 above. In other aspects, the ammonium saltof fospropofol is characterized by an XRPD pattern comprising nine peaksselected from the angles listed in Table 9 above. In other aspects, theammonium salt of fospropofol is characterized by an XRPD patterncomprising ten peaks selected from the angles listed in Table 9 above.In other aspects, the ammonium salt of fospropofol is characterized byan XRPD pattern comprising more than ten peaks selected from the angleslisted in Table 9 above.

In some embodiments, the ammonium salt of fospropofol is characterizedby an XRPD pattern comprising a peak at 18.1 degrees±0.2 degrees2-theta. In other embodiments, the ammonium salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at 18.1, 18.5, 19.2,21.1, 21.8, and 25.8 degrees±0.2 degrees 2-theta. In other embodiments,the ammonium salt of fospropofol is characterized by an XRPD patterncomprising peaks at 12.2, 14.2, 15.9, 18.1, 18.5, and 19.2 degrees±0.2degree 2-theta. In yet other embodiments, the ammonium salt offospropofol is characterized by an XRPD pattern comprising peaks at12.2, 14.2, 15.9, 18.1, 18.5, 19.2, 21.1, 21.8, and 25.8 degrees±0.2degree 2-theta.

In some embodiments of the present disclosure, the ammonium salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 12.2, 14.2, 15.9, 18.1, 18.5, 19.2, 21.1, 21.8, and25.8 degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the ammonium salt of fospropofol is characterized by an XRPDpattern comprising peaks at four or more of 12.2, 14.2, 15.9, 18.1,18.5, 19.2, 21.1, 21.8, and 25.8 degrees±0.2 degrees 2-theta. In someembodiments of the present disclosure, the ammonium salt of fospropofolis characterized by an XRPD pattern comprising peaks at five or more of12.2, 14.2, 15.9, 18.1, 18.5, 19.2, 21.1, 21.8, and 25.8 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, theammonium salt of fospropofol is characterized by an XRPD patterncomprising peaks at six or more of 12.2, 14.2, 15.9, 18.1, 18.5, 19.2,21.1, 21.8, and 25.8 degrees±0.2 degrees 2-theta. In some embodiments ofthe present disclosure, the ammonium salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at seven or more of12.2, 14.2, 15.9, 18.1, 18.5, 19.2, 21.1, 21.8, and 25.8 degrees±0.2degrees 2-theta.

The ammonium salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 58 . As FIG. 58 shows, theammonium salt of fospropofol produced endothermic peak at 76.1° C. whenheated at a rate of 10° C./min. In some embodiments of the presentdisclosure, the ammonium salt of fospropofol is characterized by a DSCthermogram comprising an endothermic peak at about 76° C. when heated ata rate of 10° C./min.

In some embodiments of the present disclosure, the ammonium salt offospropofol is characterized by an XRPD pattern comprising peaks at12.2, 14.2, 15.9, 18.1, 18.5, 19.2, 21.1, 21.8, and 25.8 degrees±0.2degrees 2-theta, and a DSC thermogram comprising an endothermic peak atabout 76° C. when heated at a rate of 10° C./min.

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the tromethamine (i.e., 2-amino-2-(hydroxymethyl)propane-1,3-diol)salt.

In some embodiments, the tromethamine salt of fospropofol has an XRPDsubstantially as shown in FIG. 59 . The XRPD of the tromethamine salt offospropofol shown in FIG. 59 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table10:

TABLE 10 XRPD Data for tromethamine salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 5.9 13.4 6.0 19.9 8.322.3 9.9 100.0 10.0 55.0 10.7 13.9 11.4 10.5 11.9 6.3 13.8 5.7 15.5 17.016.6 55.5 17.2 21.6 17.3 75.0 18.3 28.7 18.6 7.9 19.2 7.1 19.6 9.0 20.17.0 21.4 32.9 21.8 14.2 22.4 12.2 22.7 23.0 23.7 6.2 24.6 10.8 24.7 20.925.2 19.9 26.9 7.4 27.9 6.5 28.5 14.2 29.3 5.1 29.7 10.2

In some embodiments of the present disclosure, the tromethamine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 10. In other aspects, the tromethaminesalt of fospropofol is characterized by an XRPD pattern comprising morethan one peak at one of the angles listed in Table 10 above. In otheraspects, the tromethamine salt of fospropofol is characterized by anXRPD pattern comprising two peaks selected from the angles listed inTable 10 above. In other aspects, the tromethamine salt of fospropofolis characterized by an XRPD pattern comprising three peaks selected fromthe angles listed in Table 10 above. In other aspects, the tromethaminesalt of fospropofol is characterized by an XRPD pattern comprising fourpeaks selected from the angles listed in Table 10 above. In otheraspects, the tromethamine salt of fospropofol is characterized by anXRPD pattern comprising five peaks selected from the angles listed inTable 10 above. In other aspects, the tromethamine salt of fospropofolis characterized by an XRPD pattern comprising six peaks selected fromthe angles listed in Table 10 above. In other aspects, the tromethaminesalt of fospropofol is characterized by an XRPD pattern comprising sevenpeaks selected from the angles listed in Table 10 above. In otheraspects, the tromethamine salt of fospropofol is characterized by anXRPD pattern comprising eight peaks selected from the angles listed inTable 10 above. In other aspects, the tromethamine salt of fospropofolis characterized by an XRPD pattern comprising nine peaks selected fromthe angles listed in Table 10 above. In other aspects, the tromethaminesalt of fospropofol is characterized by an XRPD pattern comprising tenpeaks selected from the angles listed in Table 10 above. In otheraspects, the tromethamine salt of fospropofol is characterized by anXRPD pattern comprising more than ten peaks selected from the angleslisted in Table 10 above.

In some embodiments, the tromethamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peak at 10.0, 16.6, and17.3 degrees±0.2 degrees 2-theta. In other embodiments, the tromethaminesalt of fospropofol is characterized by an XRPD pattern comprising peaksat 10.0, 10.7, 16.6, 17.3, and 18.3 degrees±0.2 degrees 2-theta. Inother embodiments, the tromethamine salt of fospropofol is characterizedby an XRPD pattern comprising peaks at 10.0, 16.6, 17.3, 18.3, 24.7, and25.2 degrees±0.2 degree 2-theta. In yet other embodiments, thetromethamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 6.0, 10.0, 10.7, 16.6, 17.3, 18.3, 24.7, and 25.2degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the tromethamine salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 6.0, 10.0, 10.7, 16.6, 17.3, 18.3, 24.7, and 25.2degrees t 0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the tromethamine salt of fospropofol is characterized by anXRPD pattern comprising peaks at four or more of 6.0, 10.0, 10.7, 16.6,17.3, 18.3, 24.7, and 25.2 degrees±0.2 degrees 2-theta. In someembodiments of the present disclosure, the tromethamine salt offospropofol is characterized by an XRPD pattern comprising peaks at fiveor more of 6.0, 10.0, 10.7, 16.6, 17.3, 18.3, 24.7, and 25.2 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, thetromethamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at six or more of 6.0, 10.0, 10.7, 16.6, 17.3, 18.3,24.7, and 25.2 degrees±0.2 degrees 2-theta. In some embodiments of thepresent disclosure, the tromethamine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at seven or more of6.0, 10.0, 10.7, 16.6, 17.3, 18.3, 24.7, and 25.2 degrees±0.2 degrees2-theta.

The tromethamine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 60 . As FIG. 60 shows, thetromethamine salt of fospropofol produced endothermic peaks at 102.9°C., 133.3° C., and 170.5° C. when heated at a rate of 10° C./min. Insome embodiments of the present disclosure, the tromethamine salt offospropofol is characterized by a DSC thermogram comprising anendothermic peak at about 103° C., about 133° C., or about 171° C. whenheated at a rate of 10° C./min.

In some embodiments of the present disclosure, the tromethamine salt offospropofol is characterized by an XRPD pattern comprising peaks at oneor more of 6.0, 10.0, 10.7, 16.6, 17.3, 18.3, 24.7, and 25.2 degrees±0.2degrees 2-theta, and a DSC thermogram comprising an endothermic peak atabout 103° C., about 133° C., or about 171° C. when heated at a rate of10° C./min.

In some embodiments, the tromethamine salt of fospropofol can becharacterized by an NMR spectrum substantially as shown in FIG. 61 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the benethamine (i.e., N-benzyl-2-phenylethanamine) salt.

In some embodiments, the benethamine salt of fospropofol has an XRPDsubstantially as shown in FIG. 62 . The XRPD of the benethamine salt offospropofol shown in FIG. 62 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table11:

TABLE 11 XRPD Data for benethamine salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 5.5 17.0 6.6 6.9 7.215.3 8.5 10.9 9.8 4.1 10.9 4.8 11.7 14.5 12.6 13.6 14.6 5.3 16.2 33.516.4 100.0 17.1 28.1 17.7 18.4 18.0 12.0 18.3 15.4 18.8 16.2 19.5 23.519.6 24.4 20.2 14.8 21.2 7.4 21.4 7.3 21.7 15.7 21.9 14.0 23.0 8.5 23.59.9 25.5 4.8 25.8 7.4 26.5 11.0 26.7 8.5 27.8 8.3 28.1 6.5

In some embodiments of the present disclosure, the benethamine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 11. In other aspects, the benethamine saltof fospropofol is characterized by an XRPD pattern comprising more thanone peak at one of the angles listed in Table 11 above. In otheraspects, the benethamine salt of fospropofol is characterized by an XRPDpattern comprising two peaks selected from the angles listed in Table 11above. In other aspects, the benethamine salt of fospropofol ischaracterized by an XRPD pattern comprising three peaks selected fromthe angles listed in Table 11 above. In other aspects, the benethaminesalt of fospropofol is characterized by an XRPD pattern comprising fourpeaks selected from the angles listed in Table 11 above. In otheraspects, the benethamine salt of fospropofol is characterized by an XRPDpattern comprising five peaks selected from the angles listed in Table11 above. In other aspects, the benethamine salt of fospropofol ischaracterized by an XRPD pattern comprising six peaks selected from theangles listed in Table 11 above. In other aspects, the benethamine saltof fospropofol is characterized by an XRPD pattern comprising sevenpeaks selected from the angles listed in Table 11 above. In otheraspects, the benethamine salt of fospropofol is characterized by an XRPDpattern comprising eight peaks selected from the angles listed in Table11 above. In other aspects, the benethamine salt of fospropofol ischaracterized by an XRPD pattern comprising nine peaks selected from theangles listed in Table 11 above. In other aspects, the benethamine saltof fospropofol is characterized by an XRPD pattern comprising ten peaksselected from the angles listed in Table 11 above. In other aspects, thebenethamine salt of fospropofol is characterized by an XRPD patterncomprising more than ten peaks selected from the angles listed in Table11 above.

In some embodiments, the benethamine salt of fospropofol ischaracterized by an XRPD pattern comprising a peak at 16.4 degrees±0.2degrees 2-theta. In other embodiments, the benethamine salt offospropofol is characterized by an XRPD pattern comprising peaks at 8.5,11.7, 12.6, and 16.4 degrees±0.2 degrees 2-theta. In other embodiments,the benethamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 5.5, 7.2, 8.5, 11.7, 12.6, and 16.4 degrees±0.2degree 2-theta. In yet other embodiments, the benethamine salt offospropofol is characterized by an XRPD pattern comprising peaks at 5.5,7.2, 8.5, 11.7, 12.6, 16.4, 17.7, and 19.6 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the benethamine salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 5.5, 7.2, 8.5, 11.7, 12.6, 16.4, 17.7, and 19.6degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the benethamine salt of fospropofol is characterized by anXRPD pattern comprising peaks at four or more of 5.5, 7.2, 8.5, 11.7,12.6, 16.4, 17.7, and 19.6 degrees±0.2 degrees 2-theta. In someembodiments of the present disclosure, the benethamine salt offospropofol is characterized by an XRPD pattern comprising peaks at fiveor more of 5.5, 7.2, 8.5, 11.7, 12.6, 16.4, 17.7, and 19.6 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, thebenethamine salt of fospropofol is characterized by an XRPD patterncomprising peaks at six or more of 5.5, 7.2, 8.5, 11.7, 12.6, 16.4,17.7, and 19.6 degrees±0.2 degrees 2-theta.

The benethamine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 63 . As FIG. 63 shows, thebenethamine salt of fospropofol produced endothermic peaks at 85.8° C.when heated at a rate of 10° C./min. In some embodiments of the presentdisclosure, the benethamine salt of fospropofol is characterized by aDSC thermogram comprising an endothermic peak at about 86° C. whenheated at a rate of 10° C./min.

In some embodiments of the present disclosure, the benethamine salt offospropofol is characterized by an XRPD pattern comprising peaks at oneor more of 5.5, 7.2, 8.5, 11.7, 12.6, 16.4, 17.7, and 19.6 degrees±0.2degrees 2-theta, and a DSC thermogram comprising an endothermic peak atabout 86° C. when heated at a rate of 10° C./min.

In some embodiments, the benethamine salt of fospropofol can becharacterized by an NMR spectrum substantially as shown in FIG. 64 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the histadine salt.

In some embodiments, the histidine salt of fospropofol has an XRPDsubstantially as shown in FIG. 65 . The XRPD of the histidine salt offospropofol shown in FIG. 65 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table12:

TABLE 12 XRPD Data for histidine salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 5.2 79.7 9.4 11.6 11.225.7 11.7 16.3 12.0 20.3 12.4 19.0 15.3 20.8 17.8 14.3 18.9 63.5 19.613.1 21.1 74.3 21.5 100.0 23.1 15.3 24.2 60.4 25.4 12.9 26.6 10.3 29.811.7 30.2 22.3 30.9 15.9 31.4 10.0

In some embodiments of the present disclosure, the histidine salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 12. In other aspects, the histidine saltof fospropofol is characterized by an XRPD pattern comprising more thanone peak at one of the angles listed in Table 12 above. In otheraspects, the histidine salt of fospropofol is characterized by an XRPDpattern comprising two peaks selected from the angles listed in Table 12above. In other aspects, the histidine salt of fospropofol ischaracterized by an XRPD pattern comprising three peaks selected fromthe angles listed in Table 12 above. In other aspects, the histidinesalt of fospropofol is characterized by an XRPD pattern comprising fourpeaks selected from the angles listed in Table 12 above. In otheraspects, the histidine salt of fospropofol is characterized by an XRPDpattern comprising five peaks selected from the angles listed in Table12 above. In other aspects, the histidine salt of fospropofol ischaracterized by an XRPD pattern comprising six peaks selected from theangles listed in Table 12 above. In other aspects, the histidine salt offospropofol is characterized by an XRPD pattern comprising seven peaksselected from the angles listed in Table 12 above. In other aspects, thehistidine salt of fospropofol is characterized by an XRPD patterncomprising eight peaks selected from the angles listed in Table 12above. In other aspects, the histidine salt of fospropofol ischaracterized by an XRPD pattern comprising nine peaks selected from theangles listed in Table 12 above. In other aspects, the histidine salt offospropofol is characterized by an XRPD pattern comprising ten peaksselected from the angles listed in Table 12 above. In other aspects, thehistidine salt of fospropofol is characterized by an XRPD patterncomprising more than ten peaks selected from the angles listed in Table12 above.

In some embodiments, the histidine salt of fospropofol is characterizedby an XRPD pattern comprising a peak at 11.2, 15.3, and 18.9 degrees±0.2degrees 2-theta. In other embodiments, the histidine salt of fospropofolis characterized by an XRPD pattern comprising peaks at 18.9, 21.1,21.5, and 24.2 degrees±0.2 degrees 2-theta. In other embodiments, thehistidine salt of fospropofol is characterized by an XRPD patterncomprising peaks at 18.9, 21.1, 21.5, 24.2, and 30.2 degrees±0.2 degree2-theta. In yet other embodiments, the histidine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at 11.2, 15.3, 18.9,21.1, 21.5, 24.2, and 30.2 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the histidine salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 11.2, 15.3, 18.9, 21.1, 21.5, 24.2, and 30.2degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the histidine salt of fospropofol is characterized by anXRPD pattern comprising peaks at four or more of 11.2, 15.3, 18.9, 21.1,21.5, 24.2, and 30.2 degrees±0.2 degrees 2-theta. In some embodiments ofthe present disclosure, the histidine salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at five or more of11.2, 15.3, 18.9, 21.1, 21.5, 24.2, and 30.2 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the histidinesalt of fospropofol is characterized by an XRPD pattern comprising peaksat six or more of 11.2, 15.3, 18.9, 21.1, 21.5, 24.2, and 30.2degrees±0.2 degrees 2-theta.

The histidine salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 66 . As FIG. 66 shows, thehistidine salt of fospropofol produced endothermic peaks at 196.3° C.and 201.9° C. when heated at a rate of 10° C./min. In some embodimentsof the present disclosure, the histidine salt of fospropofol ischaracterized by a DSC thermogram comprising an endothermic peak atabout 196° C. or 202° C. when heated at a rate of 10° C./min.

In some embodiments of the present disclosure, the histidine salt offospropofol is characterized by an XRPD pattern comprising peaks at oneor more of 11.2, 15.3, 18.9, 21.1, 21.5, 24.2, and 30.2 degrees±0.2degrees 2-theta, and a DSC thermogram comprising an endothermic peak atabout 196° C. or 202° C. when heated at a rate of 10° C./min.

In some embodiments, the histidine salt of fospropofol can becharacterized by an NMR spectrum substantially as shown in FIG. 67 .

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the calcium salt.

In some embodiments, the calcium salt of fospropofol (Form I) has anXRPD substantially as shown in FIG. 68 . The Form I calcium salt offospropofol has a single peak at 4.7 degrees 2-theta±0.2 degrees2-theta.

In some embodiments, the Form I calcium salt of fospropofol can becharacterized by a DSC thermogram substantially as shown in FIG. 69 .

In other embodiments, the Form I calcium salt of fospropofol can becharacterized by a TGA profile substantially as shown in FIG. 69 . AsFIG. 69 shows, the Form I calcium salt of fospropofol lost about 9.5% ofits weight upon heating to 125° C., and about 41% of its weight uponheating to 325° C. a rate of 10° C./min.

In other embodiments, the calcium salt of fospropofol (Form II) has anXRPD substantially as shown in FIG. 70 . The XRPD of the Form II calciumsalt of fospropofol shown in FIG. 70 comprises reflection angles(degrees 2-theta±0.2 degrees 2-theta), and relative intensities as shownin Table 13A:

TABLE 13A XRPD Data for Form II calcium salt of Fospropofol AngleRelative (degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.3 52.7 4.532.0 5.0 100.0 5.1 52.9 7.0 7.7 7.7 11.1 8.6 4.8 9.2 17.6 12.3 4.3 12.95.9 13.9 5.3 14.4 10.5 15.6 7.1 16.3 3.4 17.1 3.9 17.8 6.5 19.4 4.6 20.03.9 20.5 3.2 21.0 4.2 21.5 4.0

In some embodiments of the present disclosure, the calcium salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 13A. In other aspects, the calcium salt offospropofol is characterized by an XRPD pattern comprising more than onepeak at one of the angles listed in Table 13A above. In other aspects,the calcium salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 13A above.In other aspects, the calcium salt of fospropofol is characterized by anXRPD pattern comprising three peaks selected from the angles listed inTable 13A above. In other aspects, the calcium salt of fospropofol ischaracterized by an XRPD pattern comprising four peaks selected from theangles listed in Table 13A above. In other aspects, the calcium salt offospropofol is characterized by an XRPD pattern comprising five peaksselected from the angles listed in Table 13A above. In other aspects,the calcium salt of fospropofol is characterized by an XRPD patterncomprising six peaks selected from the angles listed in Table 13A above.In other aspects, the calcium salt of fospropofol is characterized by anXRPD pattern comprising seven peaks selected from the angles listed inTable 13A above. In other aspects, the calcium salt of fospropofol ischaracterized by an XRPD pattern comprising eight peaks selected fromthe angles listed in Table 13A above. In other aspects, the calcium saltof fospropofol is characterized by an XRPD pattern comprising nine peaksselected from the angles listed in Table 13A above. In other aspects,the calcium salt of fospropofol is characterized by an XRPD patterncomprising ten peaks selected from the angles listed in Table 13A above.In other aspects, the calcium salt of fospropofol is characterized by anXRPD pattern comprising more than ten peaks selected from the angleslisted in Table 13A above.

In some embodiments, the calcium salt of fospropofol is characterized byan XRPD pattern comprising a peak at 5.1, 7.0, 7.7, 8.6, 9.2, and 14.4degrees t 0.2 degrees 2-theta. In other embodiments, the calcium salt offospropofol is characterized by an XRPD pattern comprising peaks at 5.0,5.1, 7.0, 7.7, 8.6, and 9.2 degrees±0.2 degrees 2-theta. In otherembodiments, the calcium salt of fospropofol is characterized by an XRPDpattern comprising peaks at 5.0, 5.1, 7.0, 7.7, 8.6, 9.2, and 14.4degrees±0.2 degree 2-theta. In yet other embodiments, the calcium saltof fospropofol is characterized by an XRPD pattern comprising peaks at4.3, 4.5, 5.0, 5.1, 7.0, 7.7, 8.6, 9.2, and 14.4 degrees±0.2 degree2-theta.

In some embodiments of the present disclosure, the calcium salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 4.3, 4.5, 5.0, 5.1, 7.0, 7.7, 8.6, 9.2, and 14.4degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the calcium salt of fospropofol is characterized by an XRPDpattern comprising peaks at four or more of 4.3, 4.5, 5.0, 5.1, 7.0,7.7, 8.6, 9.2, and 14.4 degrees 0.2 degrees 2-theta. In some embodimentsof the present disclosure, the calcium salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at five or more of4.3, 4.5, 5.0, 5.1, 7.0, 7.7, 8.6, 9.2, and 14.4 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the calcium saltof fospropofol is characterized by an XRPD pattern comprising peaks atsix or more of 4.3, 4.5, 5.0, 5.1, 7.0, 7.7, 8.6, 9.2, and 14.4degrees±0.2 degrees 2-theta.

In yet other embodiments, the calcium salt of fospropofol (Form III) hasan XRPD substantially as shown in FIG. 71 . The XRPD of the Form IIIcalcium salt of fospropofol shown in FIG. 71 comprises reflection angles(degrees 2-theta±0.2 degrees 2-theta), and relative intensities as shownin Table 13:

TABLE 13 XRPD Data for Form III calcium salt of Fospropofol AngleRelative (degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.8 100.0 9.712.0 11.6 9.3 11.9 8.8 13.2 2.9 14.5 11.3 15.3 4.0 16.1 3.2 17.2 13.018.3 3.7 19.1 3.2 19.3 3.4 19.8 3.9 21.1 5.4 21.6 4.8 23.3 2.6 24.0 3.524.8 4.9 26.5 2.6 27.3 5.2 29.1 9.3 29.6 4.6 29.8 5.7 31.2 4.2 31.7 5.934.5 3.1 34.8 4.3 35.1 3.2 38.6 5.1

In some embodiments of the present disclosure, the calcium salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 13. In other aspects, the calcium salt offospropofol is characterized by an XRPD pattern comprising more than onepeak at one of the angles listed in Table 13 above. In other aspects,the calcium salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 13 above.In other aspects, the calcium salt of fospropofol is characterized by anXRPD pattern comprising three peaks selected from the angles listed inTable 13 above. In other aspects, the calcium salt of fospropofol ischaracterized by an XRPD pattern comprising four peaks selected from theangles listed in Table 13 above. In other aspects, the calcium salt offospropofol is characterized by an XRPD pattern comprising five peaksselected from the angles listed in Table 13 above. In other aspects, thecalcium salt of fospropofol is characterized by an XRPD patterncomprising six peaks selected from the angles listed in Table 13 above.In other aspects, the calcium salt of fospropofol is characterized by anXRPD pattern comprising seven peaks selected from the angles listed inTable 13 above. In other aspects, the calcium salt of fospropofol ischaracterized by an XRPD pattern comprising eight peaks selected fromthe angles listed in Table 13 above. In other aspects, the calcium saltof fospropofol is characterized by an XRPD pattern comprising nine peaksselected from the angles listed in Table 13 above. In other aspects, thecalcium salt of fospropofol is characterized by an XRPD patterncomprising ten peaks selected from the angles listed in Table 13 above.In other aspects, the calcium salt of fospropofol is characterized by anXRPD pattern comprising more than ten peaks selected from the angleslisted in Table 13 above.

In some embodiments, the calcium salt of fospropofol is characterized byan XRPD pattern comprising a peak at 4.8, and 9.7 degrees±0.2 degrees2-theta. In other embodiments, the calcium salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at 9.7, 11.6, 11.9,14.5, and 17.2 degrees±0.2 degrees 2-theta. In other embodiments, thecalcium salt of fospropofol is characterized by an XRPD patterncomprising peaks at 11.6, 11.9, 14.5, and 17.2 degrees±0.2 degree2-theta. In yet other embodiments, the calcium salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at 4.8, 9.7, 11.6,11.9, 14.5, 17.2, and 29.1 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the calcium salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 4.8, 9.7, 11.6, 11.9, 14.5, 17.2, and 29.1 degrees 0.2degrees 2-theta. In some embodiments of the present disclosure, thecalcium salt of fospropofol is characterized by an XRPD patterncomprising peaks at four or more of 4.8, 9.7, 11.6, 11.9, 14.5, 17.2,and 29.1 degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the calcium salt of fospropofol is characterized by an XRPDpattern comprising peaks at five or more of 4.8, 9.7, 11.6, 11.9, 14.5,17.2, and 29.1 degrees±0.2 degrees 2-theta. In some embodiments of thepresent disclosure, the calcium salt of fospropofol is characterized byan XRPD pattern comprising peaks at six or more of 4.8, 9.7, 11.6, 11.9,14.5, 17.2, and 29.1 degrees±0.2 degrees 2-theta.

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the magnesium salt.

In some embodiments, the magnesium salt of fospropofol has an XRPDsubstantially as shown in FIG. 72 . The XRPD of the magnesium salt offospropofol shown in FIG. 72 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table14:

TABLE 14 XRPD Data for magnesium salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 4.5 100.0 9.1 8.8 12.23.5 13.6 10.3 15.5 6.2 18.3 4.8 20.8 5.9 24.1 3.2 27.9 5.9 31.7 3.9

In some embodiments of the present disclosure, the magnesium salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 14. In other aspects, the magnesium saltof fospropofol is characterized by an XRPD pattern comprising more thanone peak at one of the angles listed in Table 14 above. In otheraspects, the magnesium salt of fospropofol is characterized by an XRPDpattern comprising two peaks selected from the angles listed in Table 14above. In other aspects, the magnesium salt of fospropofol ischaracterized by an XRPD pattern comprising three peaks selected fromthe angles listed in Table 14 above. In other aspects, the magnesiumsalt of fospropofol is characterized by an XRPD pattern comprising fourpeaks selected from the angles listed in Table 14 above. In otheraspects, the magnesium salt of fospropofol is characterized by an XRPDpattern comprising five peaks selected from the angles listed in Table14 above. In other aspects, the magnesium salt of fospropofol ischaracterized by an XRPD pattern comprising six peaks selected from theangles listed in Table 14 above. In other aspects, the magnesium salt offospropofol is characterized by an XRPD pattern comprising seven peaksselected from the angles listed in Table 14 above. In other aspects, themagnesium salt of fospropofol is characterized by an XRPD patterncomprising eight peaks selected from the angles listed in Table 14above. In other aspects, the magnesium salt of fospropofol ischaracterized by an XRPD pattern comprising nine peaks selected from theangles listed in Table 14 above. In other aspects, the magnesium salt offospropofol is characterized by an XRPD pattern comprising ten peaksselected from the angles listed in Table 14 above. In other aspects, themagnesium salt of fospropofol is characterized by an XRPD patterncomprising more than ten peaks selected from the angles listed in Table14 above.

In some embodiments, the magnesium salt of fospropofol is characterizedby an XRPD pattern comprising a peak at 4.5 degrees±0.2 degrees 2-theta.In other embodiments, the magnesium salt of fospropofol is characterizedby an XRPD pattern comprising peaks at 4.5, 9.1, and 13.6 degrees±0.2degrees 2-theta. In other embodiments, the magnesium salt of fospropofolis characterized by an XRPD pattern comprising peaks at 4.5, 9.1, 13.6,and 20.8 degrees±0.2 degree 2-theta. In yet other embodiments, themagnesium salt of fospropofol is characterized by an XRPD patterncomprising peaks at 4.5, 9.1, 13.6, 20.8, and 27.9 degrees=0.2 degree2-theta.

In some embodiments of the present disclosure, the magnesium salt offospropofol is characterized by an XRPD pattern comprising peaks at twoor more of 4.5, 9.1, 13.6, 20.8, and 27.9 degrees±0.2 degrees 2-theta.In some embodiments of the present disclosure, the magnesium salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 4.5, 9.1, 13.6, 20.8, and 27.9 degrees±0.2 degrees2-theta. In some embodiments of the present disclosure, the magnesiumsalt of fospropofol is characterized by an XRPD pattern comprising peaksat four or more of 4.5, 9.1, 13.6, 20.8, and 27.9 degrees±0.2 degrees2-theta.

In some embodiments, the magnesium salt of fospropofol can becharacterized by a DSC thermogram substantially as shown in FIG. 73 . AsFIG. 73 shows, the magnesium salt of fospropofol produced an endothermicpeak at 129.0° C. when heated at a rate of 10° C./min. In someembodiments of the present disclosure, the magnesium salt of fospropofolis characterized by a DSC thermogram comprising an endothermic peak atabout 129° C. when heated at a rate of 10° C./min.

In other embodiments, the magnesium salt of fospropofol can becharacterized by a TGA profile substantially as shown in FIG. 73 . AsFIG. 73 shows, the magnesium salt of fospropofol lost about 12% of itsweight upon heating to 125° C., and about 41% of its weight upon heatingto 325° C. a rate of 10° C./min.

In some embodiments of the present disclosure, the magnesium salt offospropofol is characterized by an XRPD pattern comprising peaks at 4.5,9.1, 13.6, 20.8, and 27.9 degrees t 0.2 degrees 2-theta, and a DSCthermogram comprising an endothermic peak at about 129° C. when heatedat a rate of 10° C./min.

In some embodiments, the pharmaceutically acceptable salt of fospropofolis the zinc salt.

In some embodiments, the zinc salt of fospropofol (Form II) has an XRPDsubstantially as shown in FIG. 74 . Form II of the zinc salt has asingle peak at 4.9 degrees 2-theta±0.2 degrees 2-theta.

In some embodiments, the zinc salt of fospropofol (Form 1) has an XRPDsubstantially as shown in FIG. 75 . The XRPD of the Form I zinc salt offospropofol shown in FIG. 75 comprises reflection angles (degrees2-theta±0.2 degrees 2-theta), and relative intensities as shown in Table15:

TABLE 15 XRPD Data for Form I zinc salt of Fospropofol Angle Relative(degrees 2-theta ± 0.2 degrees 2-theta) Intensity 5.1 100.0 8.1 32.0 9.612.5 10.3 9.7 11.6 7.5 12.2 5.7 14.8 5.7 15.5 9.2 16.2 6.3 17.0 8.2 18.210.9 18.6 10.5 19.2 6.0 20.1 4.3 20.7 6.5 22.5 5.7 23.3 6.2 24.3 8.926.3 13.8

In some embodiments of the present disclosure, the Form I zinc salt offospropofol is characterized by an XRPD pattern comprising a peak at oneof the angles listed in Table 15. In other aspects, the zinc salt offospropofol is characterized by an XRPD pattern comprising more than onepeak at one of the angles listed in Table 15 above. In other aspects,the zinc salt of fospropofol is characterized by an XRPD patterncomprising two peaks selected from the angles listed in Table 15 above.In other aspects, the zinc salt of fospropofol is characterized by anXRPD pattern comprising three peaks selected from the angles listed inTable 15 above. In other aspects, the zinc salt of fospropofol ischaracterized by an XRPD pattern comprising four peaks selected from theangles listed in Table 15 above. In other aspects, the zinc salt offospropofol is characterized by an XRPD pattern comprising five peaksselected from the angles listed in Table 15 above. In other aspects, thezinc salt of fospropofol is characterized by an XRPD pattern comprisingsix peaks selected from the angles listed in Table 15 above. In otheraspects, the zinc salt of fospropofol is characterized by an XRPDpattern comprising seven peaks selected from the angles listed in Table15 above. In other aspects, the zinc salt of fospropofol ischaracterized by an XRPD pattern comprising eight peaks selected fromthe angles listed in Table 15 above. In other aspects, the zinc salt offospropofol is characterized by an XRPD pattern comprising nine peaksselected from the angles listed in Table 15 above. In other aspects, thezinc salt of fospropofol is characterized by an XRPD pattern comprisingten peaks selected from the angles listed in Table 15 above. In otheraspects, the zinc salt of fospropofol is characterized by an XRPDpattern comprising more than ten peaks selected from the angles listedin Table 15 above.

In some embodiments, the Form I zinc salt of fospropofol ischaracterized by an XRPD pattern comprising a peak at 8.1, 9.6, and 10.3degrees±0.2 degrees 2-theta. In other embodiments, the zinc salt offospropofol is characterized by an XRPD pattern comprising peaks at18.2, 18.6, and 26.3 degrees±0.2 degrees 2-theta. In other embodiments,the zinc salt of fospropofol is characterized by an XRPD patterncomprising peaks at 8.1, 9.6, 10.3, 11.6, and 12.2 degrees±0.2 degree2-theta. In yet other embodiments, the zinc salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at 5.1, 8.1, 9.6,10.3, 11.6, 12.2, 18.2, 18.6, and 26.3 degrees±0.2 degree 2-theta.

In some embodiments of the present disclosure, the Form I zinc salt offospropofol is characterized by an XRPD pattern comprising peaks atthree or more of 5.1, 8.1, 9.6, 10.3, 11.6, 12.2, 18.2, 18.6, and 26.3degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the zinc salt of fospropofol is characterized by an XRPDpattern comprising peaks at four or more of 5.1, 8.1, 9.6, 10.3, 11.6,12.2, 18.2, 18.6, and 26.3 degrees±0.2 degrees 2-theta. In someembodiments of the present disclosure, the zinc salt of fospropofol ischaracterized by an XRPD pattern comprising peaks at five or more of5.1, 8.1, 9.6, 10.3, 11.6, 12.2, 18.2, 18.6, and 26.3 degrees±0.2degrees 2-theta. In some embodiments of the present disclosure, the zincsalt of fospropofol is characterized by an XRPD pattern comprising peaksat six or more of 5.1, 8.1, 9.6, 10.3, 11.6, 12.2, 18.2, 18.6, and 26.3degrees±0.2 degrees 2-theta. In some embodiments of the presentdisclosure, the zinc salt of fospropofol is characterized by an XRPDpattern comprising peaks at seven or more of 5.1, 8.1, 9.6, 10.3, 11.6,12.2, 18.2, 18.6, and 26.3 degrees±0.2 degrees 2-theta.

The Form I zinc salt of fospropofol can be characterized by a DSCthermogram substantially as shown in FIG. 76 . As FIG. 76 shows, thezinc salt of fospropofol produced an endothermic peaks at 113.5° C. and210.3° C. when heated at a rate of 10° C./min. In some embodiments ofthe present disclosure, the zinc salt of fospropofol is characterized bya DSC thermogram comprising endothermic peaks at about 114° C. or about210° C. when heated at a rate of 10° C./min.

In other embodiments, the Form I zinc salt of fospropofol can becharacterized by a TGA profile substantially as shown in FIG. 76 . AsFIG. 76 shows, the magnesium salt of fospropofol lost about 7.4% of itsweight upon heating to 125° C., and about 44% of its weight upon heatingto 325° C. a rate of 10° C./min.

In some embodiments of the present disclosure, the Form I zinc salt offospropofol is characterized by an XRPD pattern comprising peaks at 5.1,8.1, 9.6, 10.3, 11.6, 12.2, 18.2, 18.6, and 26.3 degrees±0.2 degrees2-theta, and a DSC thermogram comprising endothermic peaks at 114° C.and 210° C. when heated at a rate of 10° C./min.

Methods of Using Fospropofol Salts

The pharmaceutically acceptable salt of fospropofol may be used in themethods of treatment disclosed herein.

In some aspects, the present disclosure is directed to methods oftreating migraine in a patient in need thereof, comprising administeringto said patient an effective amount of a pharmaceutically acceptablesalt of fospropofol wherein the pharmaceutically acceptable salt is apotassium, diethyl amine, t-butyl amine, ethylene diamine, benzathine,piperazine, ethanolamine, diethanolamine, ammonium, tromethamine,benethamine, histidine, calcium, magnesium, or zinc salt.

In some embodiments, the patient's migraine is migraine with aura.Migraine with aura is characterized by focal neurological symptoms thattypically precede, or sometimes accompany, the headache.

In other embodiments, the patient's migraine is migraine without aura.Migraine without aura is characterized by the absence of focalneurological symptoms that typically precede, or sometimes accompany,the headache.

In other embodiments, the patient's migraine is cluster headache.

In other embodiments, the patient's migraine is intractable migraine.

In some embodiments of the disclosed methods, the patient's migraine isrefractory migraine.

Refractory migraine may fail to respond one or more types ofpharmacologic treatment. Examples of pharmacologic treatment to whichrefractory migraine may fail to respond include CGRP inhibitors (e.g.,gepants, including ubrogepant and rimegepant; anti-CGRP antibodies suchas Aimovig® (erenumab); Emgality® (galcanezumab); and Ajovy®(fremanezumab); triptans (e.g., sumatriptan (Imitrex), rizatriptan(Maxalt), almotriptan (Axert), naratriptan (Amerge), zolmitriptan(Zomig), frovatriptan (Frova) and eletriptan (Relpax)), antidepressant(e.g., amitriptyline), antiseizure drugs (e.g., topirimate, valproate,and gabapentin), and NSAIDs (e.g., ibuprofen, naprozen sodium,diclofenac and ketorolac).

In some embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to CGRP inhibitors, and is referred to asCGRP inhibitor-refractory migraine.

In some embodiments, the patient's CGRP-inhibitor refractory migrainefails to respond to gepant treatment, and is referred to asgepant-refractory migraine. In other embodiments, the patient'sCGRP-inhibitor refractory migraine fails to respond to anti-CGRPantibodies, and is referred to as anti-CGRP antibody-refractorymigraine.

In other embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to triptans, and is referred to astriptan-refractory migraine.

In other embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to NSAIDs and is referred to asNSAID-refractory migraine.

In other embodiments of the disclosed methods, the patient's refractorymigraine may fail to respond to dihydroegotamine (DHE) and is referredto as DHE-refractory migraine.

In other embodiments, the patient's migraine is catemanial migraine.

In other embodiments, the patient's migraine is menstual migraine.

In some aspects, the methods of the disclosure are directed to treatingmigraine in a patient in need thereof. The methods of the disclosure,therefore, are performed on patients suffering from migraine.

In some embodiments, the patient is a mammal.

In other embodiments, the patient is a human.

In some embodiments, the patient is female.

In other embodiments, the patient is male.

In some embodiments, the patient is 18 years of age or older.

In other embodiments, the patient is between 6 and 17 years of age.

In other embodiments, the patient is less than 6 years of age.

In some embodiments, the patient was diagnosed with migraine at leastone year prior to being administered forpropofol in accordance with thedisclosed methods.

In some embodiments, the administering is oral.

In some embodiments, the administering is peroral.

In other embodiments, the administering is subcutaneous.

In other embodiments, the administering is intramuscular.

In other embodiments, the administering is intravenous.

In other embodiments, the administering is rectal.

Pharmaceutical Compositions of the Fospropofol Salts

In some aspects, the disclosure is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable salt offospropofol wherein the pharmaceutically acceptable salt is a potassium,diethyl amine, t-butyl amine, ethylene diamine, benzathine, piperazine,ethanolamine, diethanolamine, ammonium, tromethamine, benethamine,histidine, calcium, magnesium, or zinc salt, or mixtures thereof, and apharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition is a solid.

In other embodiments, the pharmaceutical composition is a liquid.

In other embodiments, the pharmaceutical composition is a suspension.

The pharmaceutical compositions of the present disclosure may take anyphysical form suitable for the mode of administration.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule (gelatin or non-gelatin), enteric capsules, cachets,tablets, beads, or powders.

In some embodiments, the physical form of the pharmaceutical compositionis coated beads.

In other embodiments, the physical form of the pharmaceuticalcomposition is tablets.

In some embodiments, the physical form of the pharmaceutical compositionis coated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis enteric coated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis multilayer tablets.

In some embodiments, the physical form of the pharmaceutical compositionis multilayer coated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis coated multilayer uncoated tablets.

In some embodiments, the physical form of the pharmaceutical compositionis a tablet within a tablet.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule containing pellets or beads.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule containing pellets or beads, wherein the pellets or beadsare heterogenous with respect to release of fospropofol.

In some embodiments, the physical form of the pharmaceutical compositionis a capsule containing tablets, wherein the tablets are heterogenouswith respect to release of fospropofol.

In other embodiments, the physical form of the pharmaceuticalcomposition is a gel, water soluble jellies, creams, lotions,suspensions, foams, powders, slurries, ointments, solutions, oils,pastes, suppositories, sprays, or emulsions.

In some embodiments, the physical form of the pharmaceutical compositionis a modified release dosage form.

In some aspects, the pharmaceutical compositions of the disclosurecomprises a pharmaceutically acceptable excipient. Pharmaceuticallyacceptable excipients for use in pharmaceutical compositions have beendescribed previously herein.

EXAMPLES Example A1

A randomized, double blind, placebo-controlled, ascending single-dose,safety-tolerability, pharmacokinetic, and efficacy study of POfospropofol administered to young healthy male and female volunteers forthe acute treatment of moderate or severe migraine headache is conductedas follows.

This study will assess the safety-tolerability, pharmacokinetics, andefficacy (pain relief) of ascending single oral (PO) doses offospropofol administered to healthy young male and female volunteers forthe acute treatment of moderate or severe migraine headache.

The study will also assess the efficacy for relief of associatedsymptoms (nausea, photophobia, phonophobia) of ascending single oraldoses of fospropofol administered to healthy young male and femalevolunteers for the acute treatment of moderate to severe migraineheadache.

Inclusion criteria: Male and female volunteers, age 18-65 yearsinclusive with an established diagnosis of migraine, with or withoutaura, according to IHS criteria. The age at the time of initial migrainediagnosis <50 yo, and the time since initial diagnisis of migraine>oneyear. The estimated frequency of migraine episodes classified asmoderate or severe is at least one per month on average over the pastyear. Subjects with coexisting headache other than migraine are eligibleprovided that these headaches are distinguishable from the subject'smigraine headaches. No relevant contraindication to use of fospropofolor propofol according to FDA approved labeling. Concomitant medicationsintended to reduce the frequency of migraine are permitted provided thatthe dose is stable for at least 3 months prior to enrolment andestimated headache frequency meets the criterion above. If concomitantmedications intended to reduce the frequency of migraine arediscontinued prior to the study, these medications must be discontinuedat least one month prior to enrolment. Patients will also have anabsence of any clinically significant medical condition that, in theopinion of the investigator or the Sponsor, may be potentiallyassociated with an increased risk from participation in the study.

Exclusion criteria: Subjects with any medical condition (e.g., sleepapnea) which, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from the administration ofstudy drug. Subjects with a contraindication to use of fospropofol orpropofol according to FDA approved labeling. Subjects with any medicalcondition, which, in the opinion of the investigator or the Sponsor, maybe potentially associated with an increased risk from participation inthe study. Subjects who require concomitant medications, the use ofwhich, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from participation in thestudy. Subjects unable or unwilling to provide informed consent. Womenof childbearing potential must be on adequate, reliable contraception.

Five separate cohorts of 12 subjects are scheduled to receive ascendingsingle PO doses of fospropofol or placebo under double-blind conditionsin five stages corresponding to planned doses of 200 mg, 600 mg, 800 mg,1000 mg, and 1200 mg. Each cohort will participate in each stage (10 toreceive fospropofol and 2 to receive placebo). Assuming the completionof five stages, the total number of subjects participating is 60 (50 toreceive fospropofol and 10 to receive placebo).

Two subjects within each cohort are randomly assigned to receiveplacebo.

Following each stage, the decision whether to progress to the next doseis based on a review of safety, tolerability and pharmacokinetic (PK)data from the preceding stage by the Safety Committee, as describedbelow.

The Safety Committee may approve dose escalation according to the doselevels planned in the protocol, may recommend against dose escalation,may recommend study of an intermediate dose level other than the doselevels planned in the protocol, or may recommend that additional data begathered at a dose level already studied.

Treatment A—200 mg Fospropofol administered as 1 capsule containing 200mg fospropofol

Treatment B—600 mg Fospropofol administered as 3 capsules, eachcontaining 200 mg fospropofol

Treatment C—800 mg Fospropofol administered as 4 capsules, eachcontaining 200 mg fospropofol

Treatment D—1000 mg Fospropofol administered as 5 capsules, eachcontaining 200 mg fospropofol

Treatment E—1200 mg Fospropofol administered as 5 capsules, eachcontaining 200 mg fospropofol

Treatment P—Placebo capsule—matching the appearance of the capsulecontaining 200 mg of fospropofol; Number of placebo capsules to dependon the dosing stage.

Within each separate cohort of 12 subjects, 10 subjects will receivesingle ascending PO doses of fospropofol at the dose levels below. Twoof the 12 subjects in each cohort will be randomly assigned to receiveplacebo.

Level Planned dose (mg) 1 200 2 600 3 800 4 1000 5 1200

1200 mg is the maximum planned dose. The dose escalation will be stoppedif there is any evidence of tolerability issues. Thus, the highest doseadministered may be lower than 1200 mg.

Following completion of each dose level, PK data collected until 9 hourspost-dose, and safety, tolerability data will be evaluated by a SafetyCommittee before proceeding to the next dose. Depending on safety andtolerability as well as available PK data, the dose escalation may bemodified such that intermediate dose levels are administered.

The Safety Committee will include at least the Qualified Investigator(QI), one medically qualified Sponsor representative, and an independentthird-party physician. Adjustments to the currently outlined dosesand/or dosing regimen may be implemented by the Safety Committee, butthe dose to be administered at a given dose level will not exceed thedose currently outlined in the protocol.

Minutes of the safety review committee meeting will be prepared andsigned by all voting participants. The minutes of the safety reviewcommittee meetings (including the decisions to escalate the dose,determination of the next dose level, increase in the safety monitoring,rationale for the decisions and supportive data) will be shared with theIndependent ethics committee(s) [IEC(s)]/Institutional review board(s)[IRB(s)] overseeing the concerned study part.

The subject's blood will be sampled pre-dose (within 15 min of dosing)and post-dose: 5, 10, 20, 30, 45, 90 minutes and 2, 4, 6, and 9 hourspost-dose. Plasma samples will be assayed for fospropofol and propofolusing validated analytical method(s) according to the principles of GoodLaboratory Practice.

The following parameters will be calculated with fospropofol andpropofol plasma concentrations: AUC0-30 min, AUC0-2h, AUC0-t, AUC0-inf,Cmax, Residual area, Tmax, T½ el, Kel, Cl/F, Vd/F, and Vd/F/kg.

Subject's will assess headache pain utilizing a 4-point Likert Scale tobe assessed at baseline (within 15 min of dosing), and post-dose at 15min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h (in clinic) andfollowing discharge (by diary) at 24 h and 48 h post-dosing. Subjectswill be asked to record by patient diary any recurrence or worsening ofheadache pain, and time of onset or worsening. (Note that a qualifyingheadache must be of at least moderate severity.)

Subjects will assess presence/absence of the most bothersome associatedsymptom for the presenting headache at baseline (within 15 min ofdosing), and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8h, 10 h (in clinic) and following discharge (by diary) at 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subject's will assess the presence/absence of nausea/vomiting,photophobia, and/or phonophobia at baseline (within 15 min of dosing),and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h(in clinic) and following discharge (by diary) at 12 h, 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subjects will be instructed to report any adverse events directly to theinvestigators or clinic staff. Subjects will be instructed to record inthe patient diary any adverse events emerging following discharge. Allsubjects will have telephone access to the investigator or investigatorstaff to report any urgent concerns in the course of the study.

In order to detect the possible emergence of any clinically significantcardiac arrhythmia or other abnormality cardiac telemetry will bemonitored from pre-dose until 10 hours post-dose. Volunteers with anyclinically significant ECG abnormality at baseline (pre-dose) will beexcluded.

Blood pressure (BP), heart rate (HR), respiratory rate (RR), and pulseoximetry will be recorded within 15 min pre-dose and at approximately 30min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing.

Modified Observer's Assessment of Alertness/Sedation (OAA/S) scorewithin 15 min pre-dose and at approximately 15 min, 30 min, and 1, 1.5,2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing will be assessed.

Hematology, biochemistry, and urinalysis will be assessed at screeningand end of study participation.

Alcohol breath test, urine cotinine determination, and urine drug screenwill be assessed at check-in.

A physical examination will be conducted at screening and end of study.An abbreviated physical exam will be conducted at clinic check-in.

Subjects will be monitored throughout the study by clinic staff foradverse events. A physician will be on site for each drug administrationand until 10 hours post-dose, and available on call for the remainder ofthe study.

This study will demonstrate that fospropofol, administered perorally, issafe and effective in treating migraine.

Example A2

Randomized, double blind, parallel group, comparative evaluation of thesafety-tolerability, pharmacokinetics, and efficacy of 3 dose regimens(2 administrations separated by 30 min) of PO fospropofol administeredto young healthy male and female volunteers for the acute treatment ofmoderate or severe migraine headache is conducted as follows.

This study will assess the safety-tolerability, pharmacokinetics, andefficacy (pain relief), in a similar population as in Example 1, ofthree dose regimens (a, b, and c), each comprising 2 PO (peroral)administrations: an initial dose followed by a second dose administered30 min later. The amount of the initial dose D1 will 400 mg. The amountof the second dose D2 will vary according to regimen a, b, and c. Theamount of the second dose D2 will be D2a=100 mg; D2b=200 mg; and D2c=400mg.

The study will also assess the efficacy for relief of associatedsymptoms (nausea, photophobia, phonophobia) of three dose regimens (a,b, and c) of fospropofol, each comprising 2 PO administrations: aninitial dose followed by a second dose administered 30 min later.

Inclusion criteria: Male and female volunteers, age 18-65 yearsinclusive with an established diagnosis of migraine, with or withoutaura, according to IHS criteria. The age at the time of initial migrainediagnosis <50 yo, and the time since initial diagnisis of migraine >oneyear. The estimated frequency of migraine episodes classified asmoderate or severe is at least one per month on average over the pastyear. Subjects with coexisting headache other than migraine are eligibleprovided that these headaches are distinguishable from the subject'smigraine headaches. No relevant contraindication to use of fospropofolor propofol according to FDA approved labeling. Concomitant medicationsintended to reduce the frequency of migraine are permitted provided thatthe dose is stable for at least 3 months prior to enrolment andestimated headache frequency meets the criterion above. If concomitantmedications intended to reduce the frequency of migraine arediscontinued prior to the study, these medications must be discontinuedat least one month prior to enrolment. Patients will also have anabsence of any clinically significant medical condition that, in theopinion of the investigator or the Sponsor, may be potentiallyassociated with an increased risk from participation in the study.

Exclusion criteria: Subjects with any medical condition (e.g., sleepapnea) which, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from the administration ofstudy drug. Subjects with a contraindication to use of fospropofol orpropofol according to FDA approved labeling. Subjects with any medicalcondition, which, in the opinion of the investigator or the Sponsor, maybe potentially associated with an increased risk from participation inthe study. Subjects who require concomitant medications, the use ofwhich, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from participation in thestudy. Subjects unable or unwilling to provide informed consent. Womenof childbearing potential must be on adequate, reliable contraception.

Randomized, double blind, parallel group, comparative evaluation of thesafety-tolerability, pharmacokinetics, and efficacy of 3 dose regimens(2 administrations separated by 30 min) of PO fospropofol administeredto young healthy male and female volunteers for the acute treatment ofmoderate or severe migraine headache.

A separate cohort of 36 subjects will be randomized to receive one of 3regimens (N=12/group) under double-blind conditions, each regimencomprising 2 PO administrations: an initial dose (same mg amount for alltreatment groups) followed by a second dose (mg amount depending on theassigned regimen) administered 30 min later. Double-blinding will bepreserved by administering an appropriate number of active and placebocapsules for the second dose.

The subject's blood will be sampled pre-dose (within 15 min of dosing)and post-dose: 5, 10, 20, 30, 45, 90 minutes and 2, 4, 6, and 9 hourspost-dose. Plasma samples will be assayed for fospropofol and propofolusing validated analytical method(s) according to the principles of GoodLaboratory Practice.

The following parameters will be calculated with fospropofol andpropofol plasma concentrations: AUC0-30 min, AUC0-2h, AUC0-t, AUC0-inf,Cmax, Residual area, Tmax, T½ el, Kel, Cl/F, Vd/F, and Vd/F/kg.

Subject's will assess headache pain utilizing a 4-point Likert Scale tobe assessed at baseline (within 15 min of dosing), and post-dose at 15min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h (in clinic) andfollowing discharge (by diary) at 24 h and 48 h post-dosing. Subjectswill be asked to record by patient diary any recurrence or worsening ofheadache pain, and time of onset or worsening. (Note that a qualifyingheadache must be of at least moderate severity.)

Subjects will assess presence/absence of the most bothersome associatedsymptom for the presenting headache at baseline (within 15 min ofdosing), and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8h, 10 h (in clinic) and following discharge (by diary) at 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subject's will assess the presence/absence of nausea/vomiting,photophobia, and/or phonophobia at baseline (within 15 min of dosing),and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h(in clinic) and following discharge (by diary) at 12 h, 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subjects will be instructed to report any adverse events directly to theinvestigators or clinic staff. Subjects will be instructed to record inthe patient diary any adverse events emerging following discharge. Allsubjects will have telephone access to the investigator or investigatorstaff to report any urgent concerns in the course of the study.

In order to detect the possible emergence of any clinically significantcardiac arrhythmia or other abnormality cardiac telemetry will bemonitored from pre-dose until 10 hours post-dose. Volunteers with anyclinically significant ECG abnormality at baseline (pre-dose) will beexcluded.

Blood pressure (BP), heart rate (HR), respiratory rate (RR), and pulseoximetry will be recorded within 15 min pre-dose and at approximately 30min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing.

Modified Observer's Assessment of Alertness/Sedation (OAA/S) scorewithin 15 min pre-dose and at approximately 15 min, 30 min, and 1, 1.5,2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing will be assessed.

Hematology, biochemistry, and urinalysis will be assessed at screeningand end of study participation.

Alcohol breath test, urine cotinine determination, and urine drug screenwill be assessed at check-in.

A physical examination will be conducted at screening and end of study.An abbreviated physical exam will be conducted at clinic check-in.

Subjects will be monitored throughout the study by clinic staff foradverse events. A physician will be on site for each drug administrationand until 10 hours post-dose, and available on call for the remainder ofthe study.

This study will demonstrate that fospropofol, administered perorally, issafe and effective in treating migraine.

Example A3

Randomized, double blind, parallel group, comparative evaluation of thesafety-tolerability, pharmacokinetics, and efficacy of 3 dose regimens(2 administrations separated by 30 min) of PO fospropofol administeredto young healthy male and female volunteers for the acute treatment ofmoderate or severe migraine headache is conducted as follows.

This study will assess the safety-tolerability, pharmacokinetics, andefficacy (pain relief), in a similar population as in Example 1, ofthree dose regimens (a, b, and c), each comprising 2 PO (peroral)administrations: an initial dose followed by a second dose administered30 min later. The amount of the initial dose D1 will 600 mg. The amountof the second dose D2 will vary according to regimen a, b, and c. Theamount of the second dose D2 will be D2a=150 mg; D2b=300 mg; and D2c=600mg.

The study will also assess the efficacy for relief of associatedsymptoms (nausea, photophobia, phonophobia) of three dose regimens (a,b, and c) of fospropofol, each comprising 2 PO administrations: aninitial dose followed by a second dose administered 30 min later.

Inclusion criteria: Male and female volunteers, age 18-65 yearsinclusive with an established diagnosis of migraine, with or withoutaura, according to IHS criteria. The age at the time of initial migrainediagnosis <50 yo, and the time since initial diagnisis of migraine >oneyear. The estimated frequency of migraine episodes classified asmoderate or severe is at least one per month on average over the pastyear. Subjects with coexisting headache other than migraine are eligibleprovided that these headaches are distinguishable from the subject'smigraine headaches. No relevant contraindication to use of fospropofolor propofol according to FDA approved labeling. Concomitant medicationsintended to reduce the frequency of migraine are permitted provided thatthe dose is stable for at least 3 months prior to enrolment andestimated headache frequency meets the criterion above. If concomitantmedications intended to reduce the frequency of migraine arediscontinued prior to the study, these medications must be discontinuedat least one month prior to enrolment. Patients will also have anabsence of any clinically significant medical condition that, in theopinion of the investigator or the Sponsor, may be potentiallyassociated with an increased risk from participation in the study.

Exclusion criteria: Subjects with any medical condition (e.g., sleepapnea) which, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from the administration ofstudy drug. Subjects with a contraindication to use of fospropofol orpropofol according to FDA approved labeling. Subjects with any medicalcondition, which, in the opinion of the investigator or the Sponsor, maybe potentially associated with an increased risk from participation inthe study. Subjects who require concomitant medications, the use ofwhich, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from participation in thestudy. Subjects unable or unwilling to provide informed consent. Womenof childbearing potential must be on adequate, reliable contraception.

Randomized, double blind, parallel group, comparative evaluation of thesafety-tolerability, pharmacokinetics, and efficacy of 3 dose regimens(2 administrations separated by 30 min) of PO fospropofol administeredto young healthy male and female volunteers for the acute treatment ofmoderate or severe migraine headache.

A separate cohort of 36 subjects will be randomized to receive one of 3regimens (N=12/group) under double-blind conditions, each regimencomprising 2 PO administrations: an initial dose (same mg amount for alltreatment groups) followed by a second dose (mg amount depending on theassigned regimen) administered 30 min later. Double-blinding will bepreserved by administering an appropriate number of active and placebocapsules for the second dose.

The subject's blood will be sampled pre-dose (within 15 min of dosing)and post-dose: 5, 10, 20, 30, 45, 90 minutes and 2, 4, 6, and 9 hourspost-dose. Plasma samples will be assayed for fospropofol and propofolusing validated analytical method(s) according to the principles of GoodLaboratory Practice.

The following parameters will be calculated with fospropofol andpropofol plasma concentrations: AUC0-30 min, AUC0-2h, AUC0-t, AUC0-inf,Cmax, Residual area, Tmax, T½ el, Kel, Cl/F, Vd/F, and Vd/F/kg.

Subject's will assess headache pain utilizing a 4-point Likert Scale tobe assessed at baseline (within 15 min of dosing), and post-dose at 15min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h (in clinic) andfollowing discharge (by diary) at 24 h and 48 h post-dosing. Subjectswill be asked to record by patient diary any recurrence or worsening ofheadache pain, and time of onset or worsening. (Note that a qualifyingheadache must be of at least moderate severity.)

Subjects will assess presence/absence of the most bothersome associatedsymptom for the presenting headache at baseline (within 15 min ofdosing), and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8h, 10 h (in clinic) and following discharge (by diary) at 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subject's will assess the presence/absence of nausea/vomiting,photophobia, and/or phonophobia at baseline (within 15 min of dosing),and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h(in clinic) and following discharge (by diary) at 12 h, 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subjects will be instructed to report any adverse events directly to theinvestigators or clinic staff Subjects will be instructed to record inthe patient diary any adverse events emerging following discharge. Allsubjects will have telephone access to the investigator or investigatorstaff to report any urgent concerns in the course of the study.

In order to detect the possible emergence of any clinically significantcardiac arrhythmia or other abnormality cardiac telemetry will bemonitored from pre-dose until 10 hours post-dose. Volunteers with anyclinically significant ECG abnormality at baseline (pre-dose) will beexcluded.

Blood pressure (BP), heart rate (HR), respiratory rate (RR), and pulseoximetry will be recorded within 15 min pre-dose and at approximately 30min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing.

Modified Observer's Assessment of Alertness/Sedation (OAA/S) scorewithin 15 min pre-dose and at approximately 15 min, 30 min, and 1, 1.5,2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing will be assessed.

Hematology, biochemistry, and urinalysis will be assessed at screeningand end of study participation.

Alcohol breath test, urine cotinine determination, and urine drug screenwill be assessed at check-in.

A physical examination will be conducted at screening and end of study.An abbreviated physical exam will be conducted at clinic check-in.

Subjects will be monitored throughout the study by clinic staff foradverse events. A physician will be on site for each drug administrationand until 10 hours post-dose, and available on call for the remainder ofthe study.

This study will demonstrate that fospropofol, administered perorally, issafe and effective in treating migraine.

Example A4

A “fospropofol tablet within a tablet” can be prepared as follows.

The core tablet contains fospropofol (200 mg; 20% by wt. dosage form),microcrystalline cellulose (100 mg; 10% by wt. of dosage form),pregelatinized starch (e.g., Starch 1500)(97.5 mg; 9.75% by weight ofdosage form), magnesium stearate (2.5 mg; 0.25% by wt. of dosage form).

The outer layer, which surrounds the core tablet, contains fospropofoldisodium (400 mg; 40% by wt. of dosage form), microcrystalline cellulose(100 mg; 10% wt. of dosage form), pregelatinized starch (e.g., Starch1500)(97.5 mg; 9.75% by wt. of dosage form), magnesium stearate (2.5 mg;0.25% by wt. of dosage form).

This is a modified-release dosage form. The outer layer dissolvesrapidly in the stomach. The core tablet dissolves slowly in the stomach,and further dissolves in the intestines.

Example A5

A “fospropofol bilayer tablet” can be prepared as follows.

One layer contains fospropofol (200 mg; 20% by wt. of bilayer tablet),microcrystalline cellulose (100 mg; 10% by wt. of bilayer tablet),pregelatinized starch (e.g., Starch 1500)(97.5 mg; 9.75% by wt. ofbilayer tablet), magnesium stearate (2.5 mg; 0.25% by wt. of bilayertablet).

The other layer contains fospropofol disodium (400 mg; 40% by wt. ofbilayer tablet), microcrystalline cellulose (100 mg; 10% by wt. ofbilayer tablet.), pregelatinized starch (e.g., Starch 1500)(97.5 mg;9.75% by wt. of bilayer tablet), magnesium stearate (2.5 mg; 0.25% bywt. of bilayer tablet).

This is a modified-release dosage form. One layer dissolves rapidly inthe stomach. The other layer dissolves slowly in the stomach, andfurther dissolves in the intestines.

Example A6

A fospropofol dosage form with immediate release and delayed releasecomponents can be prepared as follows.

The delayed release component contains fospropofol disodium (200 mg; 20%by wt. of final dosage form), microcrystalline cellulose (100 mg; 10% bywt. of final dosage form), pregelatinized starch (e.g., Starch1500)(17.5 mg; 1.75% by wt. of final dosage form), HMPC (80 mg; 8% bywt. of final dosage form), magnesium stearate (2.5 mg; 0.25% by wt. offinal dosage form).

The immediate release component contains fospropofol disodium (400 mg;40% by wt. of final dosage form), microcrystalline cellulose (100 mg;10% by wt. of final dosage form), pregelatinized starch (e.g., Starch1500)(97.5 mg; 9.75% by wt. of final dosage form), and magnesiumstearate (2.5 mg; 0.25% by wt. of final dosage form).

This is a modified-release dosage form. The delayed release componentgranules and the immediate release component granules may be combinedand pressed into a tablet, or may be combined in a capsule.

Example A7

A Fospropofol Dosage form with immediate release and enteric coatedcomponents can be prepared as follows.

The enteric coated component contains fospropofol disodium (200 mg; 20%by wt. of final dosage form), microcrystalline cellulose (100 mg; 10% bywt. of final dosage form), pregelatinized starch (e.g., Starch1500)(47.5 mg; 4.75% by wt. of final dosage form), magnesium stearate(2.5 mg; 0.25% by wt. of final dosage form), Eudragit L (50 mg; 5% bywt. of final dosage form).

The immediate release component contains fospropofol disodium (400 mg;40% by wt. of final dosage form), microcrystalline cellulose (100 mg;10% by wt. of final dosage form), pregelatinized starch (e.g., Starch1500)(97.5 mg; 9.75% by wt. of final dosage form), and magnesiumstearate (2.5 mg; 0.25% by wt. of final dosage form).

This is a modified-release dosage form. The enteric coated componentgranules and the immediate release component granules or beads may becombined and pressed into a tablet, or may be combined in a capsule.

Example A8

Randomized, double blind, parallel group, comparative evaluation of thesafety-tolerability, pharmacokinetics, and efficacy of 3 dosage forms ofPO fospropofol administered to young healthy male and female volunteersfor the acute treatment of moderate or severe migraine headache isconducted as follows.

This study will assess the safety-tolerability, pharmacokinetics, andefficacy (pain relief), in a similar population as in Example 1, of asingle administration of one of three dosage forms (the dosage forms ofExamples 5, 6, and 7).

The study will also assess the efficacy for relief of associatedsymptoms (nausea, photophobia, phonophobia) of a single administrationof one of three dosage forms (the dosage forms of Examples 5, 6, and 7).

Inclusion criteria: Male and female volunteers, age 18-65 yearsinclusive with an established diagnosis of migraine, with or withoutaura, according to IHS criteria. The age at the time of initial migrainediagnosis <50 yo, and the time since initial diagnisis of migraine >oneyear. The estimated frequency of migraine episodes classified asmoderate or severe is at least one per month on average over the pastyear. Subjects with coexisting headache other than migraine are eligibleprovided that these headaches are distinguishable from the subject'smigraine headaches. No relevant contraindication to use of fospropofolor propofol according to FDA approved labeling. Concomitant medicationsintended to reduce the frequency of migraine are permitted provided thatthe dose is stable for at least 3 months prior to enrolment andestimated headache frequency meets the criterion above. If concomitantmedications intended to reduce the frequency of migraine arediscontinued prior to the study, these medications must be discontinuedat least one month prior to enrolment. Patients will also have anabsence of any clinically significant medical condition that, in theopinion of the investigator or the Sponsor, may be potentiallyassociated with an increased risk from participation in the study.

Exclusion criteria: Subjects with any medical condition (e.g., sleepapnea) which, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from the administration ofstudy drug. Subjects with a contraindication to use of fospropofol orpropofol according to FDA approved labeling. Subjects with any medicalcondition, which, in the opinion of the investigator or the Sponsor, maybe potentially associated with an increased risk from participation inthe study. Subjects who require concomitant medications, the use ofwhich, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from participation in thestudy. Subjects unable or unwilling to provide informed consent. Womenof childbearing potential must be on adequate, reliable contraception.

A separate cohort of 36 subjects will be randomized to receive one of 3regimens (N=12/group) under double-blind conditions, each regimencomprising a single administration of one of the dosage forms of Example5, 6, or 7. Double-blinding will be preserved by administering anappropriate number of active and placebo capsules for the second dose.

The subject's blood will be sampled pre-dose (within 15 min of dosing)and post-dose: 5, 10, 20, 30, 45, 90 minutes and 2, 4, 6, and 9 hourspost-dose. Plasma samples will be assayed for fospropofol and propofolusing validated analytical method(s) according to the principles of GoodLaboratory Practice.

The following parameters will be calculated with fospropofol andpropofol plasma concentrations: AUC0-30 min, AUC0-2h, AUC0-t, AUC0-inf,Cmax, Residual area, Tmax, T½ el, Kel, Cl/F, Vd/F, and Vd/F/kg.

Subject's will assess headache pain utilizing a 4-point Likert Scale tobe assessed at baseline (within 15 min of dosing), and post-dose at 15min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h (in clinic) andfollowing discharge (by diary) at 24 h and 48 h post-dosing. Subjectswill be asked to record by patient diary any recurrence or worsening ofheadache pain, and time of onset or worsening. (Note that a qualifyingheadache must be of at least moderate severity.)

Subjects will assess presence/absence of the most bothersome associatedsymptom for the presenting headache at baseline (within 15 min ofdosing), and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8h, 10 h (in clinic) and following discharge (by diary) at 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subject's will assess the presence/absence of nausea/vomiting,photophobia, and/or phonophobia at baseline (within 15 min of dosing),and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h(in clinic) and following discharge (by diary) at 12 h, 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subjects will be instructed to report any adverse events directly to theinvestigators or clinic staff. Subjects will be instructed to record inthe patient diary any adverse events emerging following discharge. Allsubjects will have telephone access to the investigator or investigatorstaff to report any urgent concerns in the course of the study.

In order to detect the possible emergence of any clinically significantcardiac arrhythmia or other abnormality cardiac telemetry will bemonitored from pre-dose until 10 hours post-dose. Volunteers with anyclinically significant ECG abnormality at baseline (pre-dose) will beexcluded.

Blood pressure (BP), heart rate (HR), respiratory rate (RR), and pulseoximetry will be recorded within 15 min pre-dose and at approximately 30min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing.

Modified Observer's Assessment of Alertness/Sedation (OAA/S) scorewithin 15 min pre-dose and at approximately 15 min, 30 min, and 1, 1.5,2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing will be assessed.

Hematology, biochemistry, and urinalysis will be assessed at screeningand end of study participation.

Alcohol breath test, urine cotinine determination, and urine drug screenwill be assessed at check-in.

A physical examination will be conducted at screening and end of study.An abbreviated physical exam will be conducted at clinic check-in.

Subjects will be monitored throughout the study by clinic staff foradverse events. A physician will be on site for each drug administrationand until 10 hours post-dose, and available on call for the remainder ofthe study.

This study will demonstrate that each of the dosage forms of Examples 5,6, or 7, is safe and effective in treating migraine.

Example A9

Safety-tolerability and pharmacokinetics (PK) of single ascending oral(PO) doses of fospropofol disodium in healthy adult male and femalevolunteers.

-   -   Study Drug: Fospropofol Disodium    -   Study Phase and Type: Phase 1—Single Ascending Dose (SAD)    -   Study Design: Single center, Phase 1, randomized, modified        double-blind, SAD, safety-tolerability and pharmacokinetic (PK)        study of Fospropofol Disodium in healthy male and female        volunteers under fasting conditions. The study is characterized        as modified double-blind because treatment assignment will be        unblinded for review of safety-tolerability and propofol PK        following each dosing stage.        -   The study will investigate a maximum of 5 ascending dose            levels as needed. Separate cohorts of 12 subjects at each            dose level will be randomized to receive either Fospropofol            Disodium. (10 subjects) or matching placebo (2 subjects).        -   A separate cohort of 12 subjects will receive a single dose            of Fospropofol (Fospropofol Disodium) administered PO at the            highest well-tolerated dose following a standardized high            fat meal.    -   Subjects: Up to 72 healthy adult male and female subjects, ≥18        and ≤65 years of age with a body mass index (BMI) within        18.5-29.9 kg/m², inclusive. Females of childbearing potential        must be using reliable contraception.        -   Each subject will receive a single dose of Fospropofol            Disodium or a single dose of placebo. Each cohort of 12            subjects will include at least seven female subjects.        -   Subjects will not be permitted to participate in more than            one dose level. Subjects who withdraw or are withdrawn from            the study after dosing will not be replaced.    -   Screening Procedures: Demographic data, medical and medication        histories, physical examination, body measurements,        electrocardiogram (ECG), vital signs (blood pressure [BP], heart        rate [HR], respiratory rate [RR], pulse oximetry [PO], and oral        temperature [OT]), hematology, blood chemistry, human        immunodeficiency virus (HIV), hepatitis B and C tests,        urinalysis, urine drug screen, alcohol breath test, urine        cotinine test, Serum pregnancy test (women of child-bearing        potential). Screening to occur within 30 days of clinic        admission.    -   Confinements and Washout: At each dose level, 12 subjects will        be confined to the study site for at least 14 hours before        dosing.        -   At each dose level, subjects will be confined until at least            10 hours post-dose.        -   Because separate cohorts will participate at each stage,            washout is not applicable.    -   Study Drug and Dosage Form: Staring dose 200 mg.        -   Fospropofol Disodium to be administered as an appropriate            number of powder filled capsules, each capsule containing            200 mg of fospropofol disodium.        -   Placebo to be administered as an appropriate number of            matched powder filled capsules, each capsule containing a            suitable placebo.    -   Study Drug Administration: In the SAD portion of the study each        cohort of 12 subjects will receive single ascending oral doses        of Fospropofol Disodium under fasting conditions (10 subjects)        or matching placebo (2 subjects) at the planned dose levels. On        admission to the clinic, subjects who meet inclusion/exclusion        criteria will be assigned treatment (Fospropofol Disodium or        placebo) according to the randomization schedule. The site will        be informed as to which medication to be dispensed to each        particular subject at the time of the subject's randomization.        -   No food will be allowed from at least 10 hours before dosing            until at least 4 hours after dosing.        -   Fospropofol Disodium will be administered with 240 mL of            water at ambient temperature. Except for water administered            with study drug, no fluids will be allowed from before            dosing until 1 hour post-dose.        -   Following completion of each dose level, pharmacokinetic            (PK) data for propofol collected until 9 hours post-dose,            and safety and tolerability data with treatment assignment            (i.e., unblinded) collected until the clinic check-out            (approximately 10 hours post-dose) will be evaluated by a            Safety Committee before proceeding to the next dose.            Successive cohorts will be dosed at weekly intervals.        -   A separate cohort of 12 subjects will be randomized to            receive either Fospropofol Disodium. (10 subjects) or            matching placebo (2 subjects). Fospropofol Disodium will be            administered at the highest well-tolerated dose. Following            an overnight fast of at least 10 hours, subjects will start            a standardized high fat meal 30 minutes prior to            administration of study drug. Study subjects will be            requested to complete this meal within 30 minutes; however,            study drug will be administered 30 minutes after start of            the meal. Study drug will be administered with 240 mL (8            fluid ounces) of water. No food will be allowed for at least            4 hours post-dose. Except for administration in fed            condition, study procedures for the food effect cohort will            be identical to the procedures in the SAD cohorts.    -   Inclusion Criteria Male or female, non-smoker (no use of tobacco        products within 3 months prior to screening), ≥18 and ≤55 years        of age, with BMI ≥18.0 and ≤29.9 kg/m² and body weight ≥50.0 kg        -   Healthy as defined by:        -   The absence of clinically significant illness and surgery            within 4 weeks prior to dosing. Subjects vomiting within 24            hours pre-dose will be carefully evaluated. Inclusion            pre-dosing is at the discretion of the center PI.        -   The absence of clinically significant history of            neurological (other than migraine), endocrine,            cardiovascular, pulmonary, hematological, immunologic,            psychiatric, gastrointestinal, renal, hepatic, and metabolic            disease.        -   The absence of clinically significant history of sleep apnea        -   Clinical laboratory values within the laboratory acceptable            range unless values are deemed by the PI/Sub-Investigator as            “Not Clinically Significant”.        -   Ability to comprehend the nature of the study, as assessed            by the PI/Sub-Investigator. Capable of giving written            informed consent. Able to communicate effectively with            clinic staff.        -   Ability to fast for at least 10 hours and consume standard            meals.        -   Availability to volunteer for the entire study duration and            willing to adhere to all protocol requirements.        -   Female subjects must agree not to be nursing at any time            during the study and until 30 days after the study follow-up            visit.        -   Female subjects must fulfill at least one of the following:        -   Be surgically sterile for a minimum of 6 months;        -   Post-menopausal for a minimum of 1 year:        -   Agree to avoid pregnancy and use medically acceptable method            of contraception from at least 30 days prior to            administration of study drug until 30 days after the study            follow-up visit.        -   Medically acceptable methods of contraception include            hormonal contraception, hormonal or non-hormonal            intrauterine device, or double barrier method (simultaneous            use of male condom with intravaginally applied spermicide            and diaphragm or cervical cap). Complete abstinence alone            can be used as a method of contraception.    -   Exclusion Criteria Subjects to whom any of the following applies        will be excluded:        -   Any clinically significant abnormality at physical            examination, clinically significant abnormal laboratory test            results or positive serologic test for hepatitis B,            hepatitis C. or HIV found during medical screening.            (Subjects with positive serology for hepatitis C and            negative HCV RNA are eligible at the discretion of the            principal investigator.)        -   Positive urine drug screen, alcohol breath test, urine            cotinine test at screening (or at clinic check-in)        -   Positive serum pregnancy test (women of child-bearing            potential) at screening (or positive urine pregnancy test at            clinic check-in).        -   History of severe allergic reactions (e.g. anaphylactic            reactions, angioedema), hypersensitivity or idiosyncratic            reaction to fospropofol, propofol, Fospropofol Disodium            excipients or related substances.        -   Individuals having undergone any major surgery within 6            months prior to the start of the study, unless deemed            otherwise by the PI.        -   Clinically significant ECG abnormalities (e.g., QTcF>450            msec in males or >470 msec in females) or vital sign            abnormalities (systolic blood pressure lower than 95 or over            145 mmHg, diastolic blood pressure lower than 55 or over 95            mmHg, or heart rate less than 50 or over 100 bpm) at            screening.        -   Oxygen saturation by oximetry less than 93% at screening        -   History of significant alcohol abuse within one year prior            to screening or regular use of alcohol within six months            prior to the screening visit (more than fourteen units of            alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or            45 mL of 40% alcohol]).        -   History of significant drug abuse within one year prior to            screening or use of hard drugs (such as cocaine,            phencyclidine [PCP], crack, opioid derivatives including            heroin, and amphetamine derivatives) within 1 year prior to            screening.        -   Participation in an interventional clinical research study            involving the administration of an investigational or            marketed drug or device within 30 days prior to            administration of study drug or administration of a            biological product in the context of a clinical research            study within 90 days prior to administration of study drug.            Concomitant participation in an investigational study            involving no drug or device administration is permitted            provided obligations associated with the concomitant            participation are not expected to interfere with procedures            and obligations of the present study.        -   Use of medication other than topical products without            significant systemic absorption:        -   Prescription medication within 14 days prior to the first            dosing;        -   Over-the-counter products and natural health products            (including herbal remedies such as St. John's wort,            homeopathic and traditional medicines, probiotics, food            supplements such as vitamins, minerals, amino acids,            essential fatty acids, and protein supplements used in            sports) within 7 days prior to the first dosing, with the            exception of the occasional use of acetaminophen (up to 2 g            daily);        -   A depot injection or an implant of any drug within 3 months            prior to the first dosing.        -   Donation of plasma within 7 days prior to dosing. Donation            or loss of blood (excluding volume drawn at screening) of 50            mL to 499 mL of blood within 30 days, or more than 499 mL            within 56 days prior to the first dosing.        -   Hemoglobin <135 g/L for men or <120 g/L for women at            screening.        -   Intolerance to and/or difficulty with blood sampling through            venipuncture.        -   Abnormal diet patterns (for any reason) during the four            weeks preceding the study, including fasting, high protein            diets etc.        -   Employee or immediate relative of an employee of Epalex            Corporation, its affiliates or partners.    -   Study Restrictions: Subjects will be asked to refrain from using        products that may potentially affect their safety and/or the PK        of the study drug. Main study restrictions include:        -   Prescription medication from 14 days prior to dosing until            after the last PK blood sample collection of the study;        -   Over-the-counter products from 14 days prior to dosing until            after the last PK blood sample collection of the study;        -   Natural health products from 14 days pre-dose until after            the last PK blood sample collection;        -   Food containing poppy seeds within 24 hours prior to            admission of each period;        -   Alcohol-based products from 48 hours prior to dosing until            after the last PK blood sample collection (of each dose            level or period).        -   For safety reasons, subjects will be required to remain            seated or semi-reclined and avoid sleeping for the first 1            hour before and 4 hours after drug administration.    -   PK Sampling Time Points: A total of 14 blood samples (for        analysis of both fospropofol and propofol) will be collected (in        each dose level or period): Pre-dose (within 10 min of dosing)        and post-dose: 5, 10, 20, 30, 45, 60, 90 minutes and 2, 3, 4, 5,        6, and 9 hours post-dose.    -   Total Blood Volume Total blood volume per subject will not        exceed a maximum of 200 mL including screening.    -   Safety Monitoring: Medical surveillance and AE monitoring:        -   Subjects will be monitored throughout the study by Clinic            staff for AEs.        -   Continuous cardiac telemetry and pulse oximetry:        -   In order to ensure the absence of any clinically significant            cardiac arrhythmia or other abnormality at baseline            (pre-dose), cardiac telemetry will be performed from            approximately 10 hours pre-dose until dosing. Cardiac            telemetry will be continued until 9 hours post-dose to            monitor for any cardiac effects of study drug.        -   Volunteers with any clinically significant ECG abnormality            at baseline (pre-dose) will be excluded. Pulse oximetry will            be continuously monitored over the same time course.        -   Vital signs:        -   BP, HR, RR, and Pulse Oximetry (PO) will be recorded            pre-dose within 10 min of dosing and at approximately 5, 10,            20, 30, 45, 60, 90 2, 2.5, 3, 4, 6, and 9 hours after            dosing. Pulse oximetry will be continuously monitored.        -   Level of Alertness        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) Score.            See Chemik D A, Gillings D, Laine H, et al. Validity and            reliability of the Observer's Assessment of            Alertness/Sedation Scale: study with intravenous midazolam.            J Clin Psychopharmacol 1990 August; 10(4):244-51.            -   Responsiveness Score            -   Responds readily to name spoken in normal tone 5 (alert)            -   Lethargic response to name spoken in normal tone 4            -   Responds only after name is called loudly and/or 3                repeatedly            -   Responds only after mild prodding or shaking 2            -   Responds only after painful trapezius squeeze 1            -   Does not respond to painful trapezius squeeze 0        -   Sedation (MOAA/S score) will be recorded within 15 min            pre-dose, at 15 min post-dose and at approximately 15 min            intervals until 3 hours after dosing, and at 30 min            intervals thereafter until 9 hours post-dose provided that            the subject has demonstrated at least three consecutive            MOAA/S scores of 5 immediately prior to the the 3 hour            timepoint. A subject who has not demonstrated three            consecutive MOAA/S scores of 5 immediately prior to the the            3 hour timepoint will continue with MOAA/S assessments at 15            min intervals until he or she demonstrates three consecutive            MOAA/S scores of 5, with MOAA/S scores recorded at 30 min            interval thereafter until 8 hours post-dose. See Cohen LB.            Clinical trial: a dose-response study of fospropofol            disodium for moderate sedation during colonoscopy. 2008;            Aliment Pharmacol Ther 27, 597-608.        -   In addition, the bispectral (BIS) index (a commercially            available EEG-derived measure of anesthesia and sedation,            Coviden, Mansfield, Mass., USA) will be continuously            assessed from 15 min pre-dose until ˜8 h post dose using the            commercially available BIS complete 2-channel monitor. The            device uses a, disposable (single patient use), pre-gelled 4            electrode array that is applied directly to the patient's            forehead, and the procedure is minimally invasive. See            https://www.medtronic.com/covidien/en-us/products/brain-monitoring/bis-complete-2-channel-monitor.html.        -   12-lead ECG:        -   12-lead ECG will be performed on Day 1 before dosing.        -   Laboratory assessments:        -   Hematology, biochemistry, and urinalysis at check-in.        -   Alcohol breath test, urine cotinine test, and urine drug            screen at check-in.        -   Physical examination:        -   Brief physical examination: at check-in and check-out.    -   Check-out/Early Termination Procedures: The following procedures        will be done at each clinic check-out or for early termination        (when applicable): hematology, blood chemistry, urinalysis,        physical examination, vital signs, 12-lead ECG, oral        temperature, AE monitoring, urine pregnancy test for women of        child-bearing potential.    -   Analytical Method: Fospropofol and propofol will be analyzed in        plasma samples using a validated method. Additional plasma        samples may be drawn and stored for possible future bioanalysis        of other analytes.    -   Pharmacokinetic Parameters: The following pharmacokinetic        parameters will be calculated for both fospropofol and propofol        plasma concentrations: AUC_(0-t), AUC_(0-inf), C_(max), Residual        area, T_(max), T_(1/2 el), K_(el), Cl/F, Vd/F, and Vd/F/kg    -   Statistical Analyses: Statistical analyses will be performed for        the safety, tolerability and PK data

Laboratory Assessments

Hematology: Hematology will be drawn at screening, before dosing at eachdose level (at check-in or in the morning of Day −1), and at checkout,including the following: complete blood count with differential,hemoglobin, and hematocrit.

Biochemistry: Blood chemistry will be drawn at screening, before dosingat each dose level (at check-in or in the morning of Day −1), and atcheck-out, including the following: albumin, alkaline phosphatase,aspartate aminotransferase, alanine aminotransferase, urea, calcium,chloride, glucose, phosphorus, potassium, creatinine, sodium, totalbilirubin, and total protein.

Serology: Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIVantigen and antibody detection will be drawn at screening.

Urinalysis: Urine for Urinalysis at screening, before dosing at eachdose level (at check-in or in the morning of Day −1), and at check-out,including the following: macroscopic examination, pH, specific gravity,protein, glucose, ketones, bilirubin, occult blood, nitrite,urobilinogen, and leukocytes. Unless otherwise specified, microscopicexamination will be performed on abnormal findings.

Drug, Cotinine, and Alcohol Screen: A urine drug screen (amphetamines,methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol,cocaine, opiates, PCP, MDMA, methadone), a urine cotinine test, and analcohol breath test will be performed at screening and at each check-in.

Pregnancy Tests: For women of child bearing potential: A serum pregnancytest will be performed at screening. A urine pregnancy test will beperformed before dosing at each dose level (at check-in or in themorning of Day −1) and at early termination, where applicable.

Example A10

Safety-tolerability, pharmacokinetics, and efficacy of single ascendingoral doses of fospropofol disodium administered to healthy adult maleand female volunteers for the acute treatment of moderate to severemigraine headache.

-   -   Study Drug: Fospropofol Disodium    -   Study Phase and Type: Phase 2a—Single Ascending Dose (SAD) in        adults with migraine    -   Study Design: Multi-center, Phase 2a, placebo controlled,        modified double-blind, SAD, safety-tolerability, pharmacokinetic        (PK), and efficacy study of Fospropofol Disodium in adult males        and females for the acute treatment of moderate to severe        migraine headache. The study design is characterized as modified        double-blind because treatment assignment will be unblinded for        review of safety-tolerability, propofol PK, and efficacy        following each dosing stage.        -   The study will evaluate 3 ascending dose levels (in 3            stages) with dose levels to be selected on the basis of the            prior Phase 1 healthy volunteer study. Separate cohorts of            24 subjects will be randomized to receive ascending doses of            Fospropofol Disodium or matching placebo (18 of 24 subjects            to receive Fospropofol Disodium and 6 of 24 subjects to            receive placebo at each dose level). During each dosing            stage subjects and investigators will be blinded to the            treatment assignment. Following each dosing stage,            safety-tolerability, pharmacokinetic, and efficacy            assessments will be reviewed with treatment assignment            unblinded. Depending on results reviewed following Stage 1            and following Stage 2, dose escalation may stop and/or the            dose levels for subsequent stages may be modified to levels            lower than those specified in the protocol. (It is possible            that a dose level already studied will be repeated with a            subsequent cohort to provide additional information at that            dose level.) In no case will doses exceed the highest dose            level specified in the protocol.    -   Subjects: Up to 76 adult males and females ≥18 and ≤55 years of        age with a body mass index (BMI) within 18.0-35.0 kg/m²        inclusive and body weight >50 kg. Females of childbearing        potential must be using reliable contraception or totally        abstain from intercourse.        -   Separate cohorts of 24 subjects will receive Fospropofol            Disodium (18 subjects) or placebo (6) at each of three            ascending dose levels). Each cohort of 24 to be balanced on            gender 12:12, 13:11, or 14:10 with no fewer than 12 females.        -   Subjects who withdraw or are withdrawn from the study after            dosing, for reasons other than safety and tolerability, may            be replaced after consultation with the Safety Review            Committee.    -   Screening Procedures: Demographic data, medical and medication        histories including drug allergies, physical examination, body        measurements, electrocardiogram (ECG), vital signs (blood        pressure [BP], heart rate [HR], respiratory rate [RR], pulse        oximetry [PO], and oral temperature [OT]), hematology, blood        chemistry, human immunodeficiency virus (HIV), hepatitis B and C        tests, urinalysis, urine drug screen, alcohol breath test, urine        cotinine test, Serum pregnancy test (women of child-bearing        potential). Screening to occur within 30 days of clinic        admission. [Subjects who do not present with a qualifying        headache within 30 days of screening may have a second screening        visit within 45 days of the first screening at the discretion of        the investigator. Second screening visit may be abbreviated to        updated history and serum pregnancy test for women of        childbearing potential. A subject who does not present with a        qualifying headache within 30 days of the second screening will        be classified as a screening failure.]        -   Migraine History: Confirm migraine diagnosis according to            ICHD criteria, age of onset, estimated frequency of migraine            episodes, including frequency of episodes classified as            moderate or severe, history of migraine-associated symptoms            (nausea/vomiting, photophobia, phonophobia), characteristic            features of episodes including aura (if any), nature of            pain, associated symptoms; history of headache types other            than migraine, history of medications (if any) used for            treatment of acute migraine (past and current); history of            medications (if any) used for the the purpose of migraine            prophylaxis (past and current). Identification of an            appropriate “rescue” treatment (See Rescue Treatment below)    -   Confinement in clinic: Subjects will arrive at the study clinic        during the course of a migraine headache of at least moderate        severity (in the subject's judgment). Subjects will be confined        to the study site for 1 to 2 hours before dosing and confined        until at least 9 hours following a single dose of study drug.    -   Study Drug and Dosage Form: Three dose levels.        -   Fospropofol disodium to be administered as an appropriate            number of powder filled capsules, each capsule containing            200 mg of fospropofol disodium (Epalex Corporation, USA).        -   Placebo to be administered as an equivalent number of            identical capsules containing placebo.    -   Study Drug Administration: Each cohort of 24 subjects will        receive a single oral dose of either Fospropofol disodium (N=18)        or matching placebo (N=6) at one of three dose levels.        Fospropofol disodium administered as capsules containing 200 mg.        -   Subjects will receive a single dose of Fospropofol disodium            or placebo        -   Study drug will be administered with 240 mL of water at            ambient temperature. Except for water administered with            study drug, no fluids will be allowed from 1 hour before            dosing until 1 hour post-dose.        -   There will be at least 7 days between dosing of each dose            level. Following completion of each dose level,            pharmacokinetic (PK) data for propofol collected until 9            hours post-dose, safety and tolerability data collected            until the clinic check-out (approximately 10 hours            post-dose), and the efficacy data collected until 9 hours            post-dose will be evaluated by a Safety Committee before            proceeding to the next dose.    -   Inclusion Criteria Male or female, non-smoker (no use of tobacco        products within 3 months prior to screening), ≥18 and ≤55 years        of age, with BMI ≥18.0 and ≤35.0 kg/m² and body weight ≥50.0 kg        Generally healthy (other than migraine) as defined by:        -   The absence of clinically significant illness and surgery            within 4 weeks prior to dosing. Subjects vomiting within 24            hours pre-dose will be carefully evaluated. Inclusion            pre-dosing is at the discretion of the center PI.        -   The absence of clinically significant history of            neurological (other than migraine), endocrine,            cardiovascular, pulmonary, hematological, immunologic,            psychiatric, gastrointestinal, renal, hepatic, and metabolic            disease.        -   The absence of clinically significant history of sleep apnea        -   Subject has at least 1 year history of migraines (with or            without aura), consistent with a diagnosis according to the            International Classification of Headache Disorder, 3rd            Edition, Beta version including the following:        -   Migraine attacks present for more than 1 year with age of            onset prior to 50 years of age        -   Migraine attacks last, 4 to 72 hours if untreated, on            average, in the 3 months prior to screening visit        -   Two to eight (2-8) moderate or severe migraine attacks per            month in the 3 months prior to the screening visit. The            migraine, for which the patient receives treatment during            the study, must have at least one of the associated            symptoms: nausea, photophobia, phonophobia, or migraine with            aura        -   Subjects on prophylactic migraine medication are permitted            to remain on therapy provided they have been on a stable            dose for at least 3 months prior to screening visit and the            dose is not expected to change during the course of the            study        -   Clinical laboratory values within the laboratory acceptable            range unless values are deemed by the PI/Sub-Investigator as            “Not Clinically Significant”.        -   Ability to comprehend the nature of the study, as assessed            by the PI/Sub-Investigator. Capable of giving written            informed consent. Able to communicate effectively with            clinic staff.        -   Availability to volunteer for the entire study duration and            willing to adhere to all protocol requirements.        -   Female subjects must agree not to be nursing at any time            during the study and until 30 days after the study follow-up            visit.        -   Female subjects must fulfill at least one of the following:        -   Be surgically sterile for a minimum of 6 months;        -   Post-menopausal for a minimum of 1 year;        -   Agree to avoid pregnancy and use medically acceptable method            of contraception from at least 30 days prior to            administration of study drug until 30 days after the study            follow-up visit.        -   Medically acceptable methods of contraception include            hormonal contraception, hormonal or non-hormonal            intrauterine device, or double barrier method (simultaneous            use of male condom with intravaginally applied spermicide            and diaphragm or cervical cap). Complete abstinence alone            can be used as a method of contraception.        -   Subjects with coexisting history of headache other than            migraine are eligible provided that these headaches are            distinguishable from the subject's migraine headaches        -   No contraindication to use of fospropofol according to FDA            approved labeling        -   Concomitant medications taken for the purpose of migraine            prophylaxis are permitted provided that the dose of these            medications is stable for at least 3 months prior to            administration of study drug and estimated headache            frequency at screening meets the criterion above        -   If concomitant medications intended to reduce the frequency            of migraine are discontinued prior to the study, these            medications must be discontinued at least one month prior to            receiving study drug        -   Absence of any medical condition that, in the opinion of the            investigator or the Sponsor, may be potentially associated            with an increased risk from study drug or participation in            the study.        -   Subject must be willing to avoid the use of analgesics or            any acute migraine medication(s) for 24 hours prior to            receiving study drug.        -   Subject must be willing to forgo rescue treatment (defined            below) for at least 2 hours after initiation of treatment            with study drug.    -   Exclusion Criteria Subjects to whom any of the following applies        will be excluded:        -   Patient has basilar migraine or hemiplegic migraine        -   Patient is taking narcotic (opiate) medication        -   Patient uses an opiate as first line acute treatment for            migraine attacks        -   History of ergotamine, triptan, or any acute therapy intake            on ≥10 days per month on a regular basis for ≥3 months        -   History of simple analgesic intake on ≥10 days per month for            ≥3 months        -   History of use of opioid or combination medication intake or            butalbital containing analgesic greater than 5 days per            month for ≥3 months        -   Very frequent chronic tension type headaches for 15 or more            days per month (or unable to distinguish between            tension-type headaches and migraine)        -   Patient has major depression, other pain syndromes that            might interfere with study assessments, psychiatric            conditions, dementia, or significant neurological disorders            (other than migraine)        -   Any clinically significant abnormality at physical            examination, clinically significant abnormal laboratory test            results or positive serologic test for hepatitis B,            hepatitis C, or HIV found during medical screening.            (Subjects with positive serology for hepatitis C and            negative HCV RNA are eligible at the discretion of the            principal investigator.)        -   Positive urine drug screen (unless consistent with an            ongoing prescription drug as documented by the center            investigator), positive alcohol breath test, urine cotinine            test at screening or at clinic check-in        -   Positive serum pregnancy test (women of child-bearing            potential) at screening (or positive urine pregnancy test at            clinic check-in).        -   History of severe allergic reactions (e.g. anaphylactic            reactions, angioedema), hypersensitivity or idiosyncratic            reaction to fospropofol, propofol, Fospropofol Disodium            excipients or related substances.        -   Individuals having undergone any major surgery within 6            months prior to the start of the study, unless deemed            otherwise by the PI.        -   Clinically significant ECG abnormalities (e.g., QTcF>450            msec in males or >470 msec in females) or persistent (3            determinations) vital sign abnormalities at screening            (systolic blood pressure lower than 90 or over 145 mmHg,            diastolic blood pressure lower than 55 or over 95 mmHg, or            heart rate less than 50 or over 100 bpm). Vital signs to be            taken in a seated position and may be repeated up to a total            of three determinations.        -   Oxygen saturation by oximetry less than 93% at screening        -   History of significant alcohol abuse within one year prior            to screening or regular use of alcohol within six months            prior to the screening visit (more than fourteen units of            alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or            45 mL of 40% alcohol]).        -   History of significant drug abuse within one year prior to            screening or use of hard drugs (such as cocaine,            phencyclidine [PCP], crack, opioid derivatives including            heroin, and amphetamine derivatives) within 1 year prior to            screening.        -   Participation in an interventional clinical research study            involving the administration of an investigational or            marketed drug or device within 30 days prior to            administration of study drug or administration of a            biological product in the context of a clinical research            study within 90 days prior to administration of study drug.            Concomitant participation in an investigational study            involving no drug or device administration is permitted            provided obligations associated with the concomitant            participation are not expected to interfere with procedures            and obligations of the present study.        -   Any medical condition (other than migraine) requiring            ongoing, more than occasional, use of analgesic drugs.            (Occasional use of acetaminophen, aspirin, or NSAID, or            topical products without significant systemic absorption is            not an exclusion).        -   Any medical condition requiring ongoing treatment with            sedative-hypnotic drugs (e.g., benzodiazepines,            barbiturates)        -   Donation of plasma within 7 days prior to dosing. Donation            or loss of blood (excluding volume drawn at screening) of 50            mL to 499 mL of blood within 30 days, or more than 499 mL            within 56 days prior to the first dosing.        -   Hemoglobin <135 g/L for men or <120 g/L for women at            screening.        -   Intolerance to and/or difficulty with blood sampling through            venipuncture.        -   Abnormal diet patterns (for any reason) during the four            weeks preceding the study, including fasting, high protein            diets etc.        -   Employee or immediate relative of an employee of Epalex            Corporation, its affiliates or partners.    -   Study Restrictions: Subjects will be asked to refrain from using        products that may potentially affect their safety, the PK        profile of the study drug, and/or assessments of efficacy. Main        study restrictions include the following:        -   Analgesic drugs, e.g., opiates alone or in a combination            product from screening until the end-of-study follow-up            visit. Occasional use of acetaminophen, aspirin, or an NSAID            will be permitted; however, a subject will not be eligible            to receive study drug if he/she has taken any analgesic            (including over the counter) in the preceding 24 hours.            Analgesics (except as rescue) are not permitted from 24            hours prior to clinic admission until the end-of-study            follow-up visit.        -   Marijuana products including THC and CBD are not permitted            from screening until the end-of-study follow-up visit.        -   Sedative-hypnotic drugs, prescription or OTC, (e.g.,            benzodiazepines, barbiturates, sleeping aids, Fiorinal) from            screening until the end-of-study follow-up visit.        -   Triptans, e.g., sumatriptan, Imitrex (except as rescue,            where applicable) are not permitted from screening until the            end-of-study follow-up visit.        -   Ergotamine or combination drugs, containing ergotamine e.g.            cafergot (except as rescue, where applicable) from screening            until the end-of-study follow-up visit.        -   Metoclopramide, e.g. Reglan (except as rescue, where            applicable) from screening until the end-of-study follow-up            visit.        -   Alcohol-based products are permitted; however, a subject            will not be eligible to receive study drug if he/she has            taken any alcohol-based product in the preceding 24 hours.            Alcohol-based products are not permitted from 24 hours prior            to clinic admission until the end-of-study follow-up visit.        -   Prescription and OTC medications that are medically            necessary (except analgesics, sedative-hypnotics, and drugs            intended for treatment of acute migraine, as described            above) are permitted. The center principal investigator (PI)            will review, record, and approve at screening the            concomitant medications expected to be continued over the            course of study. In case of questions as to the suitability            of a concomitant medication, investigators are encouraged to            consult with the Sponsor.        -   For safety reasons, subjects will be required to remain            seated or semi-reclined and avoid sleeping for the first 1            hour before and 4 hours after administration of study drug.    -   PK Sampling Time Points: A total of 14 blood samples (for        analysis of both fospropofol and propofol) will be collected (in        each dose level or period): Pre-dose (within 10 min of dosing)        and post-dose: 5, 10, 20, 30, 45, 60, 90 minutes and 2, 3, 4, 5,        6, and 9 hours post-dose.    -   Subject Safety Monitoring: Medical surveillance and AE        monitoring:        -   Subjects will be monitored throughout the study by Clinic            staff for AEs.        -   Continuous cardiac telemetry and pulse oximetry:        -   To detect any clinically significant cardiac arrhythmia or            other abnormality at baseline (pre-dose), cardiac telemetry            will be performed for at least 30 minutes prior to dosing            and continued until approximately 9 hours post-dose to            monitor for any cardiac effects of study drug. Subjects with            any clinically significant ECG abnormality at baseline            (pre-dose) will be excluded. Pulse oximetry will be            monitored over the same time course.        -   Vital signs:        -   BP, HR, RR, and Pulse Oximetry (PO) will be recorded            pre-dose within 10 min of dosing and at approximately 5, 10,            20, 30, 45, 60, 90 2, 2.5, 3, 4, 6, and 9 hours after            dosing.        -   Level of Alertness        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) Score.            See Chemik DA, Gillings D, Laine H, et al. Validity and            reliability of the Observer's Assessment of            Alertness/Sedation Scale: study with intravenous midazolam.            J Clin Psychopharmacol 1990 August; 10(4):244-51.        -   Responsiveness Score        -   Responds readily to name spoken in normal tone 5 (alert)        -   Lethargic response to name spoken in normal tone 4        -   Responds only after name is called loudly and/or 3            repeatedly        -   Responds only after mild prodding or shaking 2        -   Responds only after painful trapezius squeeze 1        -   Does not respond to painful trapezius squeeze 0        -   Sedation (MOAA/S score) will be recorded within 10 min            pre-dose and at approximately 5 min intervals until 3 hours            after dosing, and at 15 min intervals thereafter until 9            hours post-dose provided that the subject has demonstrated            at least three consecutive MOAA/S scores of 5 immediately            prior to the the 3 hour timepoint. A subject who has not            demonstrated three consecutive MOAA/S scores of 5            immediately prior to the the 3 hour timepoint will continue            with MOAA/S assessments at 5 min intervals until he or she            demonstrates three consecutive MOAA/S scores of 5, with            MOAA/S scores recorded at 15 min intervals thereafter until            9 hours post-dose. See Cohen LB. Clinical trial: a            dose-response study of fospropofol disodium for moderate            sedation during colonoscopy. 2008; Aliment Pharmacol Ther            27, 597-608.        -   12-lead ECG:        -   12-lead ECG will be performed at Clinic check-in (Day 1,            before dosing) and at Clinic checkout.        -   Laboratory Assessments:        -   Hematology, biochemistry, and urinalysis at clinic check-in            and at the follow-up (final) visit to be scheduled between            48 h and 96 h after administration of study drug.        -   Alcohol breath test, urine cotinine test, and urine drug            screen at check-in.        -   For women of child-bearing potential, urine pregnancy test            at check-in; serum pregnancy test at follow-up (final) visit            scheduled between 48 h and 96 h after administration of            study drug [A serum pregnancy test will be obtained at            screening.]        -   Physical examination:        -   Complete physical exam (PE) at screening, brief PE at clinic            check-in and clinic checkout; complete PE at follow-up            (final) visit scheduled between 48 h and 96 h after            administration of study drug    -   Clinic Check-in Food will not be permitted from the time of        clinic check-in until 4 hours after dosing of study drug. Fluids        will not be permitted from one hour before until one hour after        administration of study drug (except for water (240 mL)        administered with study drug.) Water will be permitted ad lib at        all other times.        -   Abbreviated physical exam, alcohol breath test, and urine            drug screen at check-in. Urine pregnancy test (women of            child-bearing potential)        -   Record time and nature of last meal or food intake        -   Record concomitant medications and all medications taken in            the 24 hours prior to check-in.        -   Record characteristics of the presenting headache and            associated symptoms including, but not limited to the            following:        -   Characteristics of the presenting headache (i.e., throbbing,            unilateral or bilateral, aggravated by exercise,).        -   Subject's assessment of headache pain at admission to clinic            on a 4-point Likert Scale, (i.e., 0=none, 1=mild,            2=moderate, 3=severe) for the presenting headache.        -   Most bothersome associated symptom for the presenting            headache (e.g., nausea/vomiting, photophobia, phonophobia)        -   Presence of associated symptoms, nausea, vomiting,            photophobia, phonophobia (Yes/No) at clinic admission    -   Efficacy Measures: Subject's assessment of headache pain—4-point        Likert Scale (Severe, Moderate, Mild, No pain) to be assessed at        baseline prior to dosing (within 10 min of dosing), and        post-dose at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3        h, 4 h, 6 h, 8 h, and at clinic discharge, and following        discharge (by diary) at 12, 24 h and 48 h post-dosing. Headache        qualifying for treatment with study drug must be of at least        moderate severity at baseline (pre-dose and within 10 min of        dosing study drug). Subjects will be asked to announce while in        clinic the time that no headache pain is first noted, or, after        discharge, if applicable, to record the time that no headache        pain is first noted in the patient diary. Subjects will also be        asked to announce in clinic and/or record by patient diary after        discharge from clinic any recurrence or worsening of headache        pain, and time of onset of worsening.        -   Subject's assessment of presence/absence of most bothersome            symptom (MBS)—subjects to be questioned as to presence or            absence of the most bothersome symptom associated with            presenting headache (identified at clinic admission) at the            same time points as the assessment of headache pain            [baseline prior to dosing (within 10 min of dosing), and            post-dose at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h,            3 h, 4 h, 6 h, 8 h, and at clinic discharge, and following            discharge (by diary) at 12, 24 h and 48 h            post-dosing.]Subjects will also be asked to announce while            in clinic the time that disappearance of the most bothersome            symptom is first noted, or, after discharge, if applicable,            to record the time that no headache pain is first noted in            the patient diary. Subjects will also be asked to announce            in clinic and/or record by patient diary after discharge            from clinic any recurrence of the most bothersome symptom,            and time of onset of recurrence.        -   Subject assessment of presence/absence of            migraine-associated symptoms (other than MBS):            nausea/vomiting, photophobia, and/or phonophobia at baseline            (within 15 min of dosing), and post-dose at 5 min, 15 min,            30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and at            clinic discharge, and following discharge (by diary) at 12,            24 h and 48 h post-dosing. Subjects will also be asked to            announce while in clinic the time that disappearance of            migraine-associated symptoms is first noted, or, after            discharge, if applicable, to record the time that            disappearance of the associated symptom is first noted in            the patient diary. Subjects will also be asked to announce            in clinic and/or record by patient diary after discharge            from clinic any recurrence of a migraine-associated symptom,            and time of onset of recurrence.        -   While in clinic subjects will be instructed to report any            adverse events directly to the investigators or clinic            staff. Subjects will be instructed to record in the patient            diary any adverse events emerging following discharge. All            subjects will have telephone access to the investigator or            investigator staff to report any urgent concerns in the            course of the study.    -   Rescue Treatment Rescue treatment (acute treatment for migraine        pain) may be administered at any time at the investigator's        discretion. Subjects and investigators will be encouraged to        avoid administration of rescue treatment earlier than 2 hours        after administration of study drug. Rescue treatment may include        an analgesic and/or acute migraine medication(s). Selection of        rescue for each subject may be guided by history of treatment        effective for the subject in the past. In general, the        investigator and subject will have agreed on the appropriate        rescue therapy for the subject at screening. In identifying an        appropriate rescue therapy, the additive cardiorespiratory        effects of narcotic analgesics and sedative hypnotic agents when        administered concomitantly with fospropofol should be        considered.    -   Clinic Check-out: The following procedures will be carried out        at clinic check-out: physical examination, vital signs, 12-lead        ECG, oral temperature, AE monitoring. Distribute diary for        subjects to record and grade any ongoing headache pain, and any        ongoing migraine-associated symptoms (present/absent), and/or        any recurrence or worsening of pain or migraine-associated        symptoms. Schedule follow-up visit.    -   Follow-up Visit/End of Study Participation The following        procedures will be carried out at a follow-up end of study visit        to be scheduled 48 to 96 hours after administration of study        drug: hematology, blood chemistry, urinalysis, AE monitoring,        serum pregnancy test for women of child-bearing potential    -   Analytical Method: Fospropofol and propofol will be analyzed in        plasma samples using a validated method. Additional plasma        samples may be drawn and stored for possible future bioanalysis        of other analytes.    -   Pharmacokinetic Parameters: The following pharmacokinetic        parameters will be calculated for both fospropofol and propofol        plasma concentrations: AUC_(0-t), AUC_(0-inf), C_(max), Residual        area, T_(max), T_(1/2 el), K_(el), Cl/F, Vd/F, and Vd/F/kg    -   Statistical Analyses: Statistical analyses will be performed        with the safety, tolerability, efficacy, and PK data.

Laboratory Assessments—Example A10

Hematology: Hematology will be drawn at screening, at clinic check-in,and at the follow-up (final) visit. Hematology will include completeblood count with differential, hemoglobin, and hematocrit.

Chemistry: Blood chemistry will be drawn at screening, at cliniccheck-in, and at the follow-up (final) visit. Blood chemistry willinclude albumin, alkaline phosphatase, aspartate aminotransferase,alanine aminotransferase, urea, calcium, chloride, glucose, phosphorus,potassium, creatinine, sodium, total bilirubin, and total protein.

Serology: Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIVantigen and antibody detection will be drawn at screening.

Urinalysis: Urine for Urinalysis will be taken at screening, at cliniccheck-in, and at the follow-up (final) visit. Urinalysis will includemacroscopic examination, pH, specific gravity, protein, glucose,ketones, bilirubin, occult blood, nitrite, urobilinogen, and leukocytes.Unless otherwise specified, microscopic examination will be performed onabnormal findings.

Drug, Cotinine, and Alcohol Screen: A urine drug screen (amphetamines,methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol,cocaine, opiates, PCP, MDMA, methadone), a urine cotinine test, and analcohol breath test will be performed at screening and at cliniccheck-in.

Pregnancy Tests: For women of child bearing potential: A serum pregnancytest will be performed at screening. A urine pregnancy test will beperformed at clinic check-in. A serum pregnancy test will be performedat the follow-up (final) visit, and at early termination, whereapplicable.

Example A11

Safety-tolerability, pharmacokinetics, and efficacy of single pulsedascending oral doses of fospropofol disodium administered to adult malesand females for the acute treatment of moderate to severe migraineheadache.

-   -   Study Drug: Fospropofol disodium    -   Study Phase and Type: Phase 2a—Single Pulsed Ascending Dose        (SAD) in adults with migraine    -   Study Design: Multi-center, Phase 2a, placebo controlled,        modified double-blind, Single Pulsed Ascending Dose,        safety-tolerability, pharmacokinetic (PK), and efficacy study of        Fospropofol disodium in adult males and females for the acute        treatment of moderate to severe migraine headache. The study is        characterized as modified double-blind because treatment        assignment will be unblinded for review of safety-tolerability,        propofol PK, and efficacy following each dosing stage.        -   The study will evaluate 3 ascending dose levels of a pulsed            dose (in 3 stages) with dose levels to be selected on the            basis of the prior Phase 2a SAD study in subjects with acute            migraine (Study Fospropofol Disodium-02A). Separate cohorts            of 16 subjects will be randomized to receive a fixed dose            (all subjects) followed by ascending pulsed doses of            Fospropofol disodium or matching placebo (12 of 16 subjects            to receive a pulsed dose of Fospropofol disodium and 4 of 16            subjects to receive a pulsed dose of placebo at each dose            level). During each dosing stage subjects and investigators            will be blinded to the treatment assignment.    -   Subjects: Up to 52 adult males and females ≥18 and ≤55 years of        age with a body mass index (BMI) within 18.0-35.0 kg/m²        inclusive and body weight >50 kg. Females of childbearing        potential must be using reliable contraception or totally        abstain from intercourse.        -   Three separate cohorts of 16 subjects will receive a fixed            dose of Fospropofol Disodium followed by a second “pulsed”            dose of EP-102 30 minutes later (12 subjects) or a second            “pulsed” dose of placebo 30 minutes (4 subjects) at each of            three ascending dose levels. Each cohort of 16 to be            balanced on gender 8:8 or 9:7 with no fewer than 8 females.        -   Subjects who withdraw or are withdrawn from the study after            dosing, for reasons other than safety and tolerability, may            be replaced after consultation with the Safety Review            Committee.    -   Screening Procedures: Demographic data, medical and medication        histories including drug allergies, physical examination, body        measurements, electrocardiogram (ECG), vital signs (blood        pressure [BP], heart rate [HR], respiratory rate [RR], pulse        oximetry [PO], and oral temperature [OT]), hematology, blood        chemistry, human immunodeficiency virus (HIV), hepatitis B and C        tests, urinalysis, urine drug screen, alcohol breath test, urine        cotinine test, Serum pregnancy test (women of child-bearing        potential). Screening to occur within 30 days of clinic        admission. [Subjects who do not present with a qualifying        headache within 30 days of screening may have a second screening        visit within 45 days of the first screening at the discretion of        the investigator. Second screening visit may be abbreviated to        updated history and serum pregnancy test for women of        childbearing potential. A subject who does not present with a        qualifying headache within 30 days of the second screening will        be classified as a screening failure.]        -   Migraine History: Confirm migraine diagnosis according to            ICHD criteria, age of onset, estimated frequency of migraine            episodes, including frequency of episodes classified as            moderate or severe, history of migraine-associated symptoms            (nausea/vomiting, photophobia, phonophobia), characteristic            features of episodes including aura (if any), nature of            pain, associated symptoms; history of headache types other            than migraine, history of medications (if any) used for            treatment of acute migraine (past and current); history of            medications (if any) used for the the purpose of migraine            prophylaxis (past and current). Identification of an            appropriate “rescue” treatment (See Rescue Treatment below)    -   Confinement in clinic: Subjects will arrive at the study clinic        during the course of a migraine headache of at least moderate        severity (in the subject's judgment). Subjects will be confined        to the study site for 1 to 2 hours before dosing and confined        until at least 9 hours following the initial dose of study drug.    -   Study Drug and Dosage Form: Fixed dose for the initial dose (all        stages) and three ascending active dose levels for the second        (pulsed) dose        -   Fospropofol disodium to be administered as an appropriate            number of powder filled capsules, each capsule containing            200 mg of fospropofol disodium and/or 100 mg of fospropofol            disodium (Epalex Corporation, USA).        -   Placebo to be administered (second “pulsed” dose) as an            equivalent number of identical capsules containing placebo.    -   Study Drug Administration: Each cohort of 16 subjects will        receive the same single fixed oral dose of Fospropofol disodium        (N=16) as the initial dose. After 30 minutes, subjects will        receive a second “pulsed” dose of Fospropofol disodium (N=12) or        matching placebo (N-4). The amount of the second “pulsed” dose        will increase at each stage (ascending dose design). Fospropofol        disodium will be administered as capsules containing 200 mg        and/or 100 mg of fospropofol disodium (Fospropofol disodium) to        achieve the planned dose.        -   Study drug (each of the two administrations) will be            administered with 240 mL of water at ambient temperature.            Except for water administered with study drug, no fluids            will be allowed from 1 hour before dosing until 1 hour            post-dose.        -   There will be at least 7 days between dosing of each dose            level. Following completion of each dose level,            pharmacokinetic (PK) data for propofol collected until 9            hours post-dose (where time post-dose refers to the time            interval from the initial dose), safety and tolerability            data collected until the clinic check-out (approximately 10            hours post-dose), and the efficacy data collected until 9            hours post-dose will be evaluated by a Safety Committee            before proceeding to the next dose.    -   Inclusion Criteria Male or female, non-smoker (no use of tobacco        products within 3 months prior to screening), ≥18 and ≤55 years        of age, with BMI ≥18.0 and ≤32.0 kg/m² and body weight ≥50.0 kg        -   Generally healthy (other than migraine) as defined by:        -   The absence of clinically significant illness and surgery            within 4 weeks prior to dosing. Subjects vomiting within 24            hours pre-dose will be carefully evaluated. Inclusion            pre-dosing is at the discretion of the center PI.        -   The absence of clinically significant history of            neurological (other than migraine), endocrine,            cardiovascular, pulmonary, hematological, immunologic,            psychiatric, gastrointestinal, renal, hepatic, and metabolic            disease.        -   The absence of clinically significant history of sleep apnea        -   Subject has at least 1 year history of migraines (with or            without aura), consistent with a diagnosis according to the            International Classification of Headache Disorder, 3rd            Edition, Beta version including the following:        -   Migraine attacks present for more than 1 year with age of            onset prior to 50 years of age        -   Migraine attacks last, 4 to 72 hours if untreated, on            average, in the 3 months prior to screening visit        -   Two to eight (2-8) moderate or severe migraine attacks per            month in the 3 months prior to the screening visit. The            migraine, for which the patient receives treatment during            the study, must have at least one of the associated            symptoms: nausea, photophobia, phonophobia, or migraine with            aura        -   Subjects on prophylactic migraine medication are permitted            to remain on therapy provided they have been on a stable            dose for at least 3 months prior to screening visit and the            dose is not expected to change during the course of the            study        -   Clinical laboratory values within the laboratory acceptable            range unless values are deemed by the PI/Sub-Investigator as            “Not Clinically Significant”.        -   Ability to comprehend the nature of the study, as assessed            by the PI/Sub-Investigator. Capable of giving written            informed consent. Able to communicate effectively with            clinic staff.        -   Availability to volunteer for the entire study duration and            willing to adhere to all protocol requirements.        -   Female subjects must agree not to be nursing at any time            during the study and until 30 days after the study follow-up            visit.        -   Female subjects must fulfill at least one of the following:        -   Be surgically sterile for a minimum of 6 months;        -   Post-menopausal for a minimum of 1 year;        -   Agree to avoid pregnancy and use medically acceptable method            of contraception from at least 30 days prior to the study            until 30 days after the study follow-up visit.        -   Medically acceptable methods of contraception include            hormonal contraception, hormonal or non-hormonal            intrauterine device, or double barrier method (simultaneous            use of male condom with intravaginally applied spermicide            and diaphragm or cervical cap).        -   Complete abstinence alone can be used as a method of            contraception.        -   Subjects with coexisting history of headache other than            migraine are eligible provided that these headaches are            distinguishable from the subject's migraine headaches        -   No contraindication to use of fospropofol according to FDA            approved labeling        -   Concomitant medications taken for the purpose of migraine            prophylaxis are permitted provided that the dose of these            medications is stable for at least 3 months prior to            administration of study drug and estimated headache            frequency at screening meets the criterion above        -   If concomitant medications intended to reduce the frequency            of migraine are discontinued prior to the study, these            medications must be discontinued at least one month prior to            receiving study drug        -   Absence of any medical condition that, in the opinion of the            investigator or the Sponsor, may be potentially associated            with an increased risk from study drug or participation in            the study.        -   Subject must be willing to avoid the use of analgesics or            any acute migraine medication(s) for 24 hours prior to            receiving study drug.        -   Subject must be willing to forgo rescue treatment (defined            below) for 2 hours after initiation of treatment with study            drug.    -   Exclusion Criteria Subjects to whom any of the following applies        will be excluded:        -   Patient has basilar migraine or hemiplegic migraine        -   Patient is taking narcotic (opiate) medication        -   Patient uses an opiate as first line acute treatment for            migraine attacks        -   History of ergotamine, triptan, or any acute therapy intake            on ≥10 days per month on a regular basis for ≥3 months        -   History of simple analgesic intake on ≥10 days per month for            ≥3 months        -   History of use of opioid or combination medication intake or            butalbital containing analgesic greater than 5 days per            month for ≥3 months        -   Very frequent chronic tension type headaches for 15 or more            days per month (or unable to distinguish between            tension-type headaches and migraine)        -   Patient has major depression, other pain syndromes that            might interfere with study assessments, psychiatric            conditions, dementia, or significant neurological disorders            (other than migraine)        -   Any clinically significant abnormality at physical            examination, clinically significant abnormal laboratory test            results or positive serologic test for hepatitis B,            hepatitis C, or HIV found during medical screening.            (Subjects with positive serology for hepatitis C and            negative HCV RNA are eligible at the discretion of the            principal investigator.)        -   Positive urine drug screen (unless consistent with an            ongoing prescription drug as documented by the center            investigator), positive alcohol breath test, urine cotinine            test at screening or at clinic check-in        -   Positive serum pregnancy test (women of child-bearing            potential) at screening (or positive urine pregnancy test at            clinic check-in).        -   History of severe allergic reactions (e.g. anaphylactic            reactions, angioedema), hypersensitivity or idiosyncratic            reaction to fospropofol, propofol, Fospropofol Disodium            excipients or related substances.        -   Individuals having undergone any major surgery within 6            months prior to the start of the study, unless deemed            otherwise by the PI.        -   Clinically significant ECG abnormalities (e.g., QTcF>450            msec in males or >470 msec in females) or persistent (3            determinations) vital sign abnormalities at screening            (systolic blood pressure lower than 90 or over 145 mmHg,            diastolic blood pressure lower than 55 or over 95 mmHg, or            heart rate less than 50 or over 100 bpm). Vital signs to be            taken in a seated position and may be repeated up to a total            of three determinations.        -   Oxygen saturation by oximetry less than 93% at screening            History of significant alcohol abuse within one year prior            to screening or regular use of alcohol within six months            prior to the screening visit (more than fourteen units of            alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or            45 mL of 40% alcohol]).        -   History of significant drug abuse within one year prior to            screening or use of hard drugs (such as cocaine,            phencyclidine [PCP], crack, opioid derivatives including            heroin, and amphetamine derivatives) within 1 year prior to            screening.        -   Participation in an interventional clinical research study            involving the administration of an investigational or            marketed drug or device within 30 days prior to            administration of study drug or administration of a            biological product in the context of a clinical research            study within 90 days prior to administration of study drug.            Concomitant participation in an investigational study            involving no drug or device administration is permitted            provided obligations associated with the concomitant            participation are not expected to interfere with procedures            and obligations of the present study.        -   Any medical condition (other than migraine) requiring            ongoing, more than occasional, use of analgesic drugs.            (Occasional use of acetaminophen, aspirin, or NSAID, or            topical products without significant systemic absorption is            not an exclusion).        -   Any medical condition requiring ongoing treatment with            sedative-hypnotic drugs (e.g., benzodiazepines,            barbiturates)        -   Donation of plasma within 7 days prior to dosing. Donation            or loss of blood (excluding volume drawn at screening) of 50            mL to 499 mL of blood within 30 days, or more than 499 mL            within 56 days prior to the first dosing.        -   Hemoglobin <135 g/L for men or <120 g/L for women at            screening.        -   Intolerance to and/or difficulty with blood sampling through            venipuncture.        -   Abnormal diet patterns (for any reason) during the four            weeks preceding the study, including fasting, high protein            diets etc.        -   Employee or immediate relative of an employee of Epalex            Corporation, its affiliates or partners    -   Study Restrictions: Analgesic drugs, e.g., opiates alone or in a        combination product from screening until the end-of-study        follow-up visit. Occasional use of acetaminophen, aspirin, or an        NSAID will be permitted; however, a subject will not be eligible        to receive study drug if he/she has taken any analgesic        (including over the counter) in the preceding 24 hours.        Analgesics (except as rescue) are not permitted from 24 hours        prior to clinic admission until the end-of-study follow-up        visit.        -   Marijuana products including THC and CBD are not permitted            from screening until the end-of-study follow-up visit.        -   Sedative-hypnotic drugs, prescription or OTC, (e.g.,            benzodiazepines, barbiturates, sleeping aids, Fiorinal) from            screening until the end-of-study follow-up visit.        -   Triptans, e.g., sumatriptan, Imitrex (except as rescue,            where applicable) are not permitted from screening until the            end-of-study follow-up visit.        -   Ergotamine or combination drugs, containing ergotamine e.g.            cafergot (except as rescue, where applicable) from screening            until the end-of-study follow-up visit.        -   Metoclopramide, e.g. Reglan (except as rescue, where            applicable) from screening until the end-of-study follow-up            visit.        -   Alcohol-based products are permitted; however, a subject            will not be eligible to receive study drug if he/she has            taken an alcohol based product in the preceding 24 hours.            Alcohol-based products are not permitted from 24 hours prior            to clinic admission until the end-of-study follow-up visit.        -   Prescription and OTC medications that are medically            necessary (except analgesics, sedative-hypnotics, and drugs            intended for treatment of acute migraine, as described            above) are permitted. The center principal investigator (PI)            will review, record, and approve at screening the            concomitant medications expected to be continued over the            course of study. In case of questions as to the suitability            of a concomitant medication, investigators are encouraged to            consult with the Sponsor.        -   For safety reasons, subjects will be required to remain            seated or semi-reclined and avoid sleeping for the first 1            hour before and 4 hours after drug administration.    -   PK Sampling Time Points: A total of 14 blood samples (for        analysis of both fospropofol and propofol) will be collected (in        each dose level or period): Pre-dose (within 10 min of dosing)        and post-dose: 5, 10, 20, 30, 45, 60, 90 minutes and 2, 3, 4, 5,        6, and 9 hours post-dose.    -   Subject Safety Monitoring: Medical surveillance and AE        monitoring:        -   Subjects will be monitored throughout the study by Clinic            staff for AEs.        -   Continuous cardiac telemetry and pulse oximetry:        -   To detect any clinically significant cardiac arrhythmia or            other abnormality at baseline (pre-dose), cardiac telemetry            will be performed for at least 30 minutes prior to dosing            and continued until approximately 9 hours post-dose to            monitor for any cardiac effects of study drug. Subjects with            any clinically significant ECG abnormality at baseline            (pre-dose) will be excluded. Pulse oximetry will be            monitored over the same time course.        -   Vital signs:        -   BP, HR, RR, and Pulse Oximetry (PO) will be recorded            pre-dose within 10 min of dosing and at approximately 5, 10,            20, 30, 45, 60, 90 2, 2.5, 3, 4, 6, and 9 hours after            dosing.        -   Level of Alertness        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) Score.            See Chemik DA, Gillings D, Laine H, et al. Validity and            reliability of the Observer's Assessment of            Alertness/Sedation Scale: study with intravenous midazolam.            J Clin Psychopharmacol 1990 August; 10(4):244-51.        -   Responsiveness Score        -   Responds readily to name spoken in normal tone 5 (alert)        -   Lethargic response to name spoken in normal tone 4        -   Responds only after name is called loudly and/or 3            repeatedly        -   Responds only after mild prodding or shaking 2        -   Responds only after painful trapezius squeeze 1        -   Does not respond to painful trapezius squeeze 0        -   Sedation (MOAA/S score) will be recorded within 10 min            pre-dose and at approximately 5 min intervals until 3 hours            after dosing, and at 15 min intervals thereafter until 9            hours post-dose provided that the subject has demonstrated            at least three consecutive MOAA/S scores of 5 immediately            prior to the the 3 hour timepoint. A subject who has not            demonstrated three consecutive MOAA/S scores of 5            immediately prior to the the 3 hour timepoint will continue            with MOAA/S assessments at 5 min intervals until he or she            demonstrates three consecutive MOAA/S scores of 5, with            MOAA/S scores recorded at 15 min interval thereafter until 9            hours post-dose. See Cohen LB. Clinical trial: a            dose-response study of fospropofol disodium for moderate            sedation during colonoscopy. 2008; Aliment Pharmacol Ther            27, 597-608.        -   12-lead ECG:        -   12-lead ECG will be performed at Clinic check-in (Day 1            before dosing) and at Clinic checkout.        -   Laboratory assessments:        -   Hematology, biochemistry, and urinalysis at clinic check-in            and at follow-up (final) visit scheduled between 48 h and 96            h after administration of study drug.        -   Alcohol breath test, urine cotinine test, and urine drug            screen at check-in.        -   For women of child-bearing potential, urine pregnancy test            at check-in; serum pregnancy test at follow-up (final) visit            scheduled between 48 h and 96 h after administration of            study drug [A serum pregnancy test will be obtained at            screening.]        -   Physical examination:        -   Complete physical exam (PE) at screening, brief PE at clinic            check-in and clinic checkout; complete PE at follow-up            (final) visit scheduled between 48 h and 96 h after            administration of study drug    -   Clinic Check-in Food will not be permitted from the time of        clinic check-in until 4 hours after the initial dosing of study        drug. Fluids will not be permitted from one hour before the        initial dose until one hour after administration of the second        (pulsed dose) of study drug (except for water (240 mL)        administered with study drug.) Water will be permitted ad lib at        all other times.        -   Abbreviated physical exam, alcohol breath test, and urine            drug screen at check-in. Urine pregnancy test (women of            child-bearing potential)        -   Record time and nature of last meal or food intake        -   Record concomitant medications and all medications taken in            the 24 hours prior to check-in.        -   Record characteristics of the presenting headache and            associated symptoms including, but not limited to the            following:        -   Characteristics of the presenting headache (i.e., throbbing,            unilateral or bilateral, aggravated by exercise,).        -   Subject's assessment of headache pain at admission to clinic            on a 4-point Likert Scale, (i.e., 0=none, 1=mild,            2=moderate, 3=severe) for the presenting headache.        -   Most bothersome associated symptom for the presenting            headache (e.g., nausea/vomiting, photophobia, phonophobia)            Presence of associated symptoms, nausea, vomiting,            photophobia, phonophobia (Yes/No) at clinic admission    -   Efficacy Measures: Note: Pre-dose and post—dose times are with        reference to the initial dose of study drug.        -   Subject's assessment of headache pain—4-point Likert Scale            (Severe, Moderate, Mild, No pain) to be assessed at baseline            prior to dosing (within 10 min of dosing), and post-dose at            5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6            h, 8 h, and at clinic discharge, and following discharge (by            diary) at 12, 24h and 48 h post-dosing. Headache qualifying            for treatment with study drug must be of at least moderate            severity at baseline (pre-dose and within 10 min of dosing            study drug). Subjects will be asked to announce while in            clinic the time that no headache pain is first noted, or,            after discharge, if applicable, to record the time that no            headache pain is first noted in the patient diary. Subjects            will also be asked to announce in clinic and/or record by            patient diary after discharge from clinic any recurrence or            worsening of headache pain, and time of onset of worsening.        -   Subject's assessment of presence/absence of most bothersome            symptom (MBS)—subjects to be questioned as to presence or            absence of the most bothersome symptom associated with            presenting headache (identified at clinic admission) at the            same time points as the assessment of headache pain            [baseline prior to dosing (within 10 min of dosing), and            post-dose at 5 min. 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h,            3 h, 4 h, 6 h, 8 h, and at clinic discharge, and following            discharge (by diary) at 12, 24 h and 48 h post-dosing.]            Subjects will also be asked to announce while in clinic the            time that disappearance of the most bothersome symptom is            first noted, or, after discharge, if applicable, to record            the time that no headache pain is first noted in the patient            diary. Subjects will also be asked to announce in clinic            and/or record by patient diary after discharge from clinic            any recurrence of the most bothersome symptom, and time of            onset of recurrence.        -   Subject assessment of presence/absence of            migraine-associated symptoms (other than MBS):            nausea/vomiting, photophobia, and/or phonophobia at baseline            (within 15 min of dosing), and post-dose at 5 min, 15 min,            30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and at            clinic discharge, and following discharge (by diary) at 12,            24 h and 48 h post-dosing. Subjects will also be asked to            announce while in clinic the time that disappearance of            migraine-associated symptoms is first noted, or, after            discharge, if applicable, to record the time that            disappearance of the associated symptom is first noted in            the patient diary. Subjects will also be asked to announce            in clinic and/or record by patient diary after discharge            from clinic any recurrence of a migraine-associated symptom,            and time of onset of recurrence.        -   While in clinic subjects will be instructed to report any            adverse events directly to the investigators or clinic            staff. Subjects will be instructed to record in the patient            diary any adverse events emerging following discharge. All            subjects will have telephone access to the investigator or            investigator staff to report any urgent concerns in the            course of the study.    -   Rescue Treatment Rescue treatment (acute treatment for migraine        pain) may be administered at any time at the investigator's        discretion. Subjects and investigators will be encouraged to        avoid administration of rescue treatment earlier than 2 hours        after initial administration of study drug. Rescue treatment may        include an analgesic and/or acute migraine medication(s).        Selection of rescue for each subject may be guided by history of        treatment effective for the subject in the past. In general, the        investigator and subject will have agreed on the appropriate        rescue therapy for the subject at screening. In identifying an        appropriate rescue therapy, the additive cardiorespiratory        effects of narcotic analgesics and sedative hypnotic agents when        administered concomitantly with fospropofol should be        considered.    -   Clinic Check-out: The following procedures will be carried out        at clinic check-out: physical examination, vital signs, 12-lead        ECG, oral temperature, AE monitoring. Distribute diary for        subjects to record and grade any ongoing headache pain, and any        ongoing migraine-associated symptoms (present/absent), and/or        any recurrence or worsening of pain or migraine-associated        symptoms. Schedule follow-up visit.    -   Follow-up Visit/End of Study Participation The following        procedures will be carried out at a follow-up end of study visit        to be scheduled 48 to 96 hours after administration of study        drug: hematology, blood chemistry, urinalysis, AE monitoring,        serum pregnancy test for women of child-bearing potential    -   Analytical Method: Fospropofol and propofol will be analyzed in        plasma samples using a validated method. Additional plasma        samples may be drawn and stored for possible future bioanalysis        of other analytes.    -   Pharmacokinetic Parameters: The following pharmacokinetic        parameters will be calculated for both fospropofol and propofol        plasma concentrations: AUC_(0-t), AUC_(0-inf), C_(max), Residual        area, T_(max), T_(1/2 el), K_(el), Cl/F, Vd/F, and Vd/F/kg    -   Statistical Analyses: Statistical analyses will be performed        with the safety, tolerability, efficacy, and PK data.

Laboratory Assessments—Example A11

Hematology: Hematology will be drawn at screening, at clinic check-in,and at the follow-up (final) visit. Hematology will include completeblood count with differential, hemoglobin, and hematocrit.

Chemistry: Blood chemistry will be drawn at screening, at cliniccheck-in, and at the follow-up (final) visit. Blood chemistry willinclude albumin, alkaline phosphatase, aspartate aminotransferase,alanine aminotransferase, urea, calcium, chloride, glucose, phosphorus,potassium, creatinine, sodium, total bilirubin, and total protein.

Serology: Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIVantigen and antibody detection will be drawn at screening.

Urinalysis: Urine for Urinalysis will be taken at screening, at cliniccheck-in, and at the follow-up (final) visit. Urinalysis will includemacroscopic examination, pH, specific gravity, protein, glucose,ketones, bilirubin, occult blood, nitrite, urobilinogen, and leukocytes.Unless otherwise specified, microscopic examination will be performed onabnormal findings.

Drug, Cotinine, and Alcohol Screen: A urine drug screen (amphetamines,methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol,cocaine, opiates, PCP, MDMA, methadone), a urine cotinine test, and analcohol breath test will be performed at screening and at cliniccheck-in.

Pregnancy Tests: For women of child bearing potential: A serum pregnancytest will be performed at screening. A urine pregnancy test will beperformed at clinic check-in. A serum pregnancy test will be performedat the follow-up (final) visit, and at early termination, whereapplicable.

Example A12

Safety-tolerability, pharmacokinetics, and efficacy of single ascendingoral doses of fospropofol disodium administered to healthy adult maleand female volunteers for the acute treatment of moderate to severemigraine headache.

-   -   Study Drug: Fospropofol Disodium    -   Study Phase and Type: Phase 2a—Single Ascending Dose (SAD) in        adults with migraine    -   Study Design: Multi-center, Phase 2a, placebo controlled,        modified double-blind, SAD, safety-tolerability, pharmacokinetic        (PK), and efficacy study of Fospropofol Disodium in adult males        and females for the acute treatment of moderate to severe        migraine headache. The study design is characterized as modified        double-blind because treatment assignment will be unblinded for        review of safety-tolerability, propofol PK, and efficacy        following each dosing stage.        -   The studywill evaluate 3 ascending dose levels (in 3 stages)            with dose levels to be selected on the basis of the prior            Phase 1 healthy volunteer study. Separate cohorts of 12-500            subjects will be randomized to receive ascending doses of            Fospropofol Disodium or matching placebo (9-375 subjects to            receive Fospropofol Disodium and 3-125 subjects to receive            placebo at each dose level). During each dosing stage            subjects and investigators will be blinded to the treatment            assignment. Following each dosing stage,            safety-tolerability, pharmacokinetic, and efficacy            assessments will be reviewed with treatment assignment            unblinded. Depending on results reviewed following Stage 1            and following Stage 2, dose escalation may stop and/or the            dose levels for subsequent stages may be modified to levels            lower than those specified in the protocol. (It is possible            that a dose level already studied will be repeated with a            subsequent cohort to provide additional information at that            dose level.) In no case will doses exceed the highest dose            level specified in the protocol.        -   Subjects: Up to 500 adult males and females ≥18 and ≤55            years of age with a body mass index (BMI) within 18.0-35.0            kg/m² inclusive and body weight >50 kg. Females of            childbearing potential must be using reliable contraception            or totally abstain from intercourse.        -   Separate cohorts of 12-500 subjects will receive Fospropofol            Disodium (9-375 subjects) or placebo (4-125) at each of            three ascending dose levels). Each cohort of 12-500 to be            balanced on gender 1:1, 1.3:1.1, or 1.4:1.0 with no fewer            than 50% females.        -   Subjects who withdraw or are withdrawn from the study after            dosing, for reasons other than safety and tolerability, may            be replaced after consultation with the Safety Review            Committee.    -   Screening Procedures: Demographic data, medical and medication        histories including drug allergies, physical examination, body        measurements, electrocardiogram (ECG), vital signs (blood        pressure [BP], heart rate [HR], respiratory rate [RR], pulse        oximetry [PO], and oral temperature [OT]), hematology, blood        chemistry, human immunodeficiency virus (HIV), hepatitis B and C        tests, urinalysis, urine drug screen, alcohol breath test, urine        cotinine test, Serum pregnancy test (women of child-bearing        potential). Screening to occur within 30 days of clinic        admission. [Subjects who do not present with a qualifying        headache within 30 days of screening may have a second screening        visit within 45 days of the first screening at the discretion of        the investigator. Second screening visit may be abbreviated to        updated history and serum pregnancy test for women of        childbearing potential. A subject who does not present with a        qualifying headache within 30 days of the second screening will        be classified as a screening failure.]        -   Migraine History: Confirm migraine diagnosis according to            ICHD criteria, age of onset, estimated frequency of migraine            episodes, including frequency of episodes classified as            moderate or severe, history of migraine-associated symptoms            (nausea/vomiting, photophobia, phonophobia), characteristic            features of episodes including aura (if any), nature of            pain, associated symptoms; history of headache types other            than migraine, history of medications (if any) used for            treatment of acute migraine (past and current); history of            medications (if any) used for the the purpose of migraine            prophylaxis (past and current). Identification of an            appropriate “rescue” treatment (See Rescue Treatment below)    -   Confinement in clinic: Subjects will arrive at the study clinic        during the course of a migraine headache of at least moderate        severity (in the subject's judgment). Subjects will be confined        to the study site for 1 to 2 hours before dosing and confined        until at least 9 hours following a single dose of study drug.    -   Study Drug and Dosage Form: Three dose levels: Selected from        within the range 200 mg-3600 mg.        -   Fospropofol Disodium to be administered as an appropriate            number of powder filled capsules, each capsule containing            200 mg of fospropofol disodium (Epalex Corporation, USA).        -   Placebo to be administered as an equivalent number of            identical capsules containing placebo.    -   Study Drug Administration: Each cohort of 12-500 subjects will        receive a single oral dose of either Fospropofol Disodium        (N=9-375) or matching placebo (N=3-125) at one of three dose        levels. Fospropofol Disodium administered as capsules containing        200 mg.        -   Subjects will receive a single dose of Fospropofol Disodium            or placebo.        -   Study drug will be administered with 240 mL of water at            ambient temperature. Except for water administered with            study drug, no fluids will be allowed from 1 hour before            dosing until 1 hour post-dose.        -   There will be at least 7 days between dosing of each dose            level. Following completion of each dose level,            pharmacokinetic (PK) data for propofol collected until 9            hours post-dose, safety and tolerability data collected            until the clinic check-out (approximately 10 hours            post-dose), and the efficacy data collected until 9 hours            post-dose will be evaluated by a Safety Committee before            proceeding to the next dose.    -   Inclusion Criteria Male or female, non-smoker (no use of tobacco        products within 3 months prior to screening), ≥18 and ≤55 years        of age, with BMI ≥18.0 and ≤35.0 kg/m² and body weight ≥50.0 kg        Generally healthy (other than migraine) as defined by:        -   The absence of clinically significant illness and surgery            within 4 weeks prior to dosing. Subjects vomiting within 24            hours pre-dose will be carefully evaluated. Inclusion            pre-dosing is at the discretion of the center PI.        -   The absence of clinically significant history of            neurological (other than migraine), endocrine,            cardiovascular, pulmonary, hematological, immunologic,            psychiatric, gastrointestinal, renal, hepatic, and metabolic            disease.        -   The absence of clinically significant history of sleep apnea        -   Subject has at least 1 year history of migraines (with or            without aura), consistent with a diagnosis according to the            International Classification of Headache Disorder, 3rd            Edition, Beta version including the following:        -   Migraine attacks present for more than 1 year with age of            onset prior to 50 years of age        -   Migraine attacks last, 4 to 72 hours if untreated, on            average, in the 3 months prior to screening visit        -   Two to eight (2-8) moderate or severe migraine attacks per            month in the 3 months prior to the screening visit. The            migraine, for which the patient receives treatment during            the study, must have at least one of the associated            symptoms: nausea, photophobia, phonophobia, or migraine with            aura        -   Subjects on prophylactic migraine medication are permitted            to remain on therapy provided they have been on a stable            dose for at least 3 months prior to screening visit and the            dose is not expected to change during the course of the            study        -   Clinical laboratory values within the laboratory acceptable            range unless values are deemed by the PI/Sub-Investigator as            “Not Clinically Significant”.        -   Ability to comprehend the nature of the study, as assessed            by the PI/Sub-Investigator. Capable of giving written            informed consent. Able to communicate effectively with            clinic staff.        -   Availability to volunteer for the entire study duration and            willing to adhere to all protocol requirements.        -   Female subjects must agree not to be nursing at any time            during the study and until 30 days after the study follow-up            visit.        -   Female subjects must fulfill at least one of the following:        -   Be surgically sterile for a minimum of 6 months;        -   Post-menopausal for a minimum of 1 year;        -   Agree to avoid pregnancy and use medically acceptable method            of contraception from at least 30 days prior to            administration of study drug until 30 days after the study            follow-up visit.        -   Medically acceptable methods of contraception include            hormonal contraception, hormonal or non-hormonal            intrauterine device, or double barrier method (simultaneous            use of male condom with intravaginally applied spermicide            and diaphragm or cervical cap). Complete abstinence alone            can be used as a method of contraception.        -   Subjects with coexisting history of headache other than            migraine are eligible provided that these headaches are            distinguishable from the subject's migraine headaches        -   No contraindication to use of fospropofol according to FDA            approved labeling        -   Concomitant medications taken for the purpose of migraine            prophylaxis are permitted provided that the dose of these            medications is stable for at least 3 months prior to            administration of study drug and estimated headache            frequency at screening meets the criterion above        -   If concomitant medications intended to reduce the frequency            of migraine are discontinued prior to the study, these            medications must be discontinued at least one month prior to            receiving study drug        -   Absence of any medical condition that, in the opinion of the            investigator or the Sponsor, may be potentially associated            with an increased risk from study drug or participation in            the study.        -   Subject must be willing to avoid the use of analgesics or            any acute migraine medication(s) for 24 hours prior to            receiving study drug.        -   Subject must be willing to forgo rescue treatment (defined            below) for at least 2 hours after initiation of treatment            with study drug.    -   Exclusion Criteria Subjects to whom any of the following applies        will be excluded:        -   Patient has basilar migraine or hemiplegic migraine        -   Patient is taking narcotic (opiate) medication        -   Patient uses an opiate as first line acute treatment for            migraine attacks        -   History of ergotamine, triptan, or any acute therapy intake            on ≥10 days per month on a regular basis for ≥3 months        -   History of simple analgesic intake on ≥10 days per month for            ≥3 months        -   History of use of opioid or combination medication intake or            butalbital containing analgesic greater than 5 days per            month for ≥3 months        -   Very frequent chronic tension type headaches for 15 or more            days per month (or unable to distinguish between            tension-type headaches and migraine)        -   Patient has major depression, other pain syndromes that            might interfere with study assessments, psychiatric            conditions, dementia, or significant neurological disorders            (other than migraine)        -   Any clinically significant abnormality at physical            examination, clinically significant abnormal laboratory test            results or positive serologic test for hepatitis B,            hepatitis C, or HIV found during medical screening.            (Subjects with positive serology for hepatitis C and            negative HCV RNA are eligible at the discretion of the            principal investigator.)        -   Positive urine drug screen (unless consistent with an            ongoing prescription drug as documented by the center            investigator), positive alcohol breath test, urine cotinine            test at screening or at clinic check-in        -   Positive serum pregnancy test (women of child-bearing            potential) at screening (or positive urine pregnancy test at            clinic check-in).        -   History of severe allergic reactions (e.g. anaphylactic            reactions, angioedema), hypersensitivity or idiosyncratic            reaction to fospropofol, propofol, Fospropofol Disodium            excipients or related substances.        -   Individuals having undergone any major surgery within 6            months prior to the start of the study, unless deemed            otherwise by the PI.        -   Clinically significant ECG abnormalities (e.g., QTcF>450            msec in males or >470 msec in females) or persistent (3            determinations) vital sign abnormalities at screening            (systolic blood pressure lower than 90 or over 145 mmHg,            diastolic blood pressure lower than 55 or over 95 mmHg, or            heart rate less than 50 or over 100 bpm). Vital signs to be            taken in a seated position and may be repeated up to a total            of three determinations.        -   Oxygen saturation by oximetry less than 93% at screening        -   History of significant alcohol abuse within one year prior            to screening or regular use of alcohol within six months            prior to the screening visit (more than fourteen units of            alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or            45 mL of 40% alcohol]).        -   History of significant drug abuse within one year prior to            screening or use of hard drugs (such as cocaine,            phencyclidine [PCP], crack, opioid derivatives including            heroin, and amphetamine derivatives) within 1 year prior to            screening.        -   Participation in an interventional clinical research study            involving the administration of an investigational or            marketed drug or device within 30 days prior to            administration of study drug or administration of a            biological product in the context of a clinical research            study within 90 days prior to administration of study drug.            Concomitant participation in an investigational study            involving no drug or device administration is permitted            provided obligations associated with the concomitant            participation are not expected to interfere with procedures            and obligations of the present study.        -   Any medical condition (other than migraine) requiring            ongoing, more than occasional, use of analgesic drugs.            (Occasional use of acetaminophen, aspirin, or NSAID, or            topical products without significant systemic absorption is            not an exclusion).        -   Any medical condition requiring ongoing treatment with            sedative-hypnotic drugs (e.g., benzodiazepines,            barbiturates)        -   Donation of plasma within 7 days prior to dosing. Donation            or loss of blood (excluding volume drawn at screening) of 50            mL to 499 mL of blood within 30 days, or more than 499 mL            within 56 days prior to the first dosing.        -   Hemoglobin <135 g/L for men or <120 g/L for women at            screening.        -   Intolerance to and/or difficulty with blood sampling through            venipuncture.        -   Abnormal diet patterns (for any reason) during the four            weeks preceding the study, including fasting, high protein            diets etc.        -   Employee or immediate relative of an employee of Epalex            Corporation, its affiliates or partners.    -   Study Restrictions: Subjects will be asked to refrain from using        products that may potentially affect their safety, the PK        profile of the study drug, and/or assessments of efficacy. Main        study restrictions include the following:        -   Analgesic drugs, e.g., opiates alone or in a combination            product from screening until the end-of-study follow-up            visit. Occasional use of acetaminophen, aspirin, or an NSAID            will be permitted; however, a subject will not be eligible            to receive study drug if he/she has taken any analgesic            (including over the counter) in the preceding 24 hours.            Analgesics (except as rescue) are not permitted from 24            hours prior to clinic admission until the end-of-study            follow-up visit.        -   Marijuana products including THC and CBD are not permitted            from screening until the end-of-study follow-up visit.        -   Sedative-hypnotic drugs, prescription or OTC, (e.g.,            benzodiazepines, barbiturates, sleeping aids, Fiorinal) from            screening until the end-of-study follow-up visit.        -   Triptans, e.g., sumatriptan, Imitrex (except as rescue,            where applicable) are not permitted from screening until the            end-of-study follow-up visit.        -   Ergotamine or combination drugs, containing ergotamine e.g.            cafergot (except as rescue, where applicable) from screening            until the end-of-study follow-up visit.        -   Metoclopramide, e.g. Reglan (except as rescue, where            applicable) from screening until the end-of-study follow-up            visit.        -   Alcohol-based products are permitted; however, a subject            will not be eligible to receive study drug if he/she has            taken any alcohol-based product in the preceding 24 hours.            Alcohol-based products are not permitted from 24 hours prior            to clinic admission until the end-of-study follow-up visit.        -   Prescription and OTC medications that are medically            necessary (except analgesics, sedative-hypnotics, and drugs            intended for treatment of acute migraine, as described            above) are permitted. The center principal investigator (PI)            will review, record, and approve at screening the            concomitant medications expected to be continued over the            course of study. In case of questions as to the suitability            of a concomitant medication, investigators are encouraged to            consult with the Sponsor.        -   For safety reasons, subjects will be required to remain            seated or semi-reclined and avoid sleeping for the first 1            hour before and 4 hours after administration of study drug.    -   PK Sampling Time Points: A total of 14 blood samples (for        analysis of both fospropofol and propofol) will be collected (in        each dose level or period): Pre-dose (within 10 min of dosing)        and post-dose: 5, 10, 20, 30, 45, 60, 90 minutes and 2, 3, 4, 5,        6, and 9 hours post-dose.    -   Subject Safety Monitoring: Medical surveillance and AE        monitoring: Subjects will be monitored throughout the study by        Clinic staff for AEs.        -   Continuous cardiac telemetry and pulse oximetrv:        -   To detect any clinically significant cardiac arrhythmia or            other abnormality at baseline (pre-dose), cardiac telemetry            will be performed for at least 30 minutes prior to dosing            and continued until approximately 9 hours post-dose to            monitor for any cardiac effects of study drug. Subjects with            any clinically significant ECG abnormality at baseline            (pre-dose) will be excluded. Pulse oximetry will be            monitored over the same time course.        -   Vital signs:        -   BP, HR, RR, and Pulse Oximetry (PO) will be recorded            pre-dose within 10 min of dosing and at approximately 5, 10,            20, 30, 45, 60, 90 2, 2.5, 3, 4, 6, and 9 hours after            dosing.        -   Level of Alertness        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) Score.            See Chemik DA, Gillings D, Laine H, et al. Validity and            reliability of the Observer's Assessment of            Alertness/Sedation Scale: study with intravenous midazolam.            J Clin Psychopharmacol 1990 August; 10(4):244-51.        -   Responsiveness Score        -   Responds readily to name spoken in normal tone 5 (alert)        -   Lethargic response to name spoken in normal tone 4        -   Responds only after name is called loudly and/or 3            repeatedly        -   Responds only after mild prodding or shaking 2        -   Responds only after painful trapezius squeeze 1        -   Does not respond to painful trapezius squeeze 0        -   Sedation (MOAA/S score) will be recorded within 10 min            pre-dose and at approximately 5 min intervals until 3 hours            after dosing, and at 15 min intervals thereafter until 9            hours post-dose provided that the subject has demonstrated            at least three consecutive MOAA/S scores of 5 immediately            prior to the the 3 hour timepoint. A subject who has not            demonstrated three consecutive MOAA/S scores of 5            immediately prior to the the 3 hour timepoint will continue            with MOAA/S assessments at 5 min intervals until he or she            demonstrates three consecutive MOAA/S scores of 5, with            MOAA/S scores recorded at 15 min intervals thereafter until            9 hours post-dose. See Cohen LB. Clinical trial: a            dose-response study of fospropofol disodium for moderate            sedation during colonoscopy. 2008; Aliment Pharmacol Ther            27, 597-608.        -   12-lead ECG:        -   12-lead ECG will be performed at Clinic check-in (Day 1,            before dosing) and at Clinic checkout.        -   Laboratory assessments:        -   Hematology, biochemistry, and urinalysis at clinic check-in            and at the follow-up (final) visit to be scheduled between            48 h and 96 h after administration of study drug.        -   Alcohol breath test, urine cotinine test, and urine drug            screen at check-in.        -   For women of child-bearing potential, urine pregnancy test            at check-in; serum pregnancy test at follow-up (final) visit            scheduled between 48 h and 96 h after administration of            study drug [A serum pregnancy test will be obtained at            screening.]        -   Physical examination:        -   Complete physical exam (PE) at screening, brief PE at clinic            check-in and clinic checkout; complete PE at follow-up            (final) visit scheduled between 48 h and 96 h after            administration of study drug    -   Clinic Check-in Food will not be permitted from the time of        clinic check-in until 4 hours after dosing of study drug. Fluids        will not be permitted from one hour before until one hour after        administration of study drug (except for water (240 mL)        administered with study drug.) Water will be permitted ad lib at        all other times.        -   Abbreviated physical exam, alcohol breath test, and urine            drug screen at check-in. Urine pregnancy test (women of            child-bearing potential)        -   Record time and nature of last meal or food intake        -   Record concomitant medications and all medications taken in            the 24 hours prior to check-in.        -   Record characteristics of the presenting headache and            associated symptoms including, but not limited to the            following:        -   Characteristics of the presenting headache (i.e., throbbing,            unilateral or bilateral, aggravated by exercise,).        -   Subject's assessment of headache pain at admission to clinic            on a 4-point Likert Scale, (i.e., 0=none, 1=mild,            2=moderate, 3=severe) for the presenting headache.        -   Most bothersome associated symptom for the presenting            headache (e.g., nausea/vomiting, photophobia, phonophobia)        -   Presence of associated symptoms, nausea, vomiting,            photophobia, phonophobia (Yes/No) at clinic admission    -   Efficacy Measures: Subject's assessment of headache pain—4-point        Likert Scale (Severe, Moderate, Mild, No pain) to be assessed at        baseline prior to dosing (within 10 min of dosing), and        post-dose at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3        h, 4 h, 6 h, 8 h, and at clinic discharge, and following        discharge (by diary) at 12, 24 h and 48 h post-dosing. Headache        qualifying for treatment with study drug must be of at least        moderate severity at baseline (pre-dose and within 10 min of        dosing study drug). Subjects will be asked to announce while in        clinic the time that no headache pain is first noted, or, after        discharge, if applicable, to record the time that no headache        pain is first noted in the patient diary. Subjects will also be        asked to announce in clinic and/or record by patient diary after        discharge from clinic any recurrence or worsening of headache        pain, and time of onset of worsening.        -   Subject's assessment of presence/absence of most bothersome            symptom (MBS)—subjects to be questioned as to presence or            absence of the most bothersome symptom associated with            presenting headache (identified at clinic admission) at the            same time points as the assessment of headache pain            [baseline prior to dosing (within 10 min of dosing), and            post-dose at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h,            3 h, 4 h, 6 h, 8 h, and at clinic discharge, and following            discharge (by diary) at 12, 24 h and 48 h            post-dosing.]Subjects will also be asked to announce while            in clinic the time that disappearance of the most bothersome            symptom is first noted, or, after discharge, if applicable,            to record the time that no headache pain is first noted in            the patient diary. Subjects will also be asked to announce            in clinic and/or record by patient diary after discharge            from clinic any recurrence of the most bothersome symptom,            and time of onset of recurrence.        -   Subject assessment of presence/absence of            migraine-associated symptoms (other than MBS):            nausea/vomiting, photophobia, and/or phonophobia at baseline            (within 15 min of dosing), and post-dose at 5 min, 15 min,            30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and at            clinic discharge, and following discharge (by diary) at 12,            24 h and 48 h post-dosing. Subjects will also be asked to            announce while in clinic the time that disappearance of            migraine-associated symptoms is first noted, or, after            discharge, if applicable, to record the time that            disappearance of the associated symptom is first noted in            the patient diary. Subjects will also be asked to announce            in clinic and/or record by patient diary after discharge            from clinic any recurrence of a migraine-associated symptom,            and time of onset of recurrence.        -   While in clinic subjects will be instructed to report any            adverse events directly to the investigators or clinic            staff. Subjects will be instructed to record in the patient            diary any adverse events emerging following discharge. All            subjects will have telephone access to the investigator or            investigator staff to report any urgent concerns in the            course of the study.    -   Rescue Treatment Rescue treatment (acute treatment for migraine        pain) may be administered at any time at the investigator's        discretion. Subjects and investigators will be encouraged to        avoid administration of rescue treatment earlier than 2 hours        after administration of study drug. Rescue treatment may include        an analgesic and/or acute migraine medication(s). Selection of        rescue for each subject may be guided by history of treatment        effective for the subject in the past. In general, the        investigator and subject will have agreed on the appropriate        rescue therapy for the subject at screening. In identifying an        appropriate rescue therapy, the additive cardiorespiratory        effects of narcotic analgesics and sedative hypnotic agents when        administered concomitantly with fospropofol should be        considered.    -   Clinic Check-out: The following procedures will be carried out        at clinic check-out: physical examination, vital signs, 12-lead        ECG, oral temperature, AE monitoring. Distribute diary for        subjects to record and grade any ongoing headache pain, and any        ongoing migraine-associated symptoms (present/absent), and/or        any recurrence or worsening of pain or migraine-associated        symptoms. Schedule follow-up visit.    -   Follow-up Visit/End of Study Participation The following        procedures will be carried out at a follow-up end of study visit        to be scheduled 48 to 96 hours after administration of study        drug: hematology, blood chemistry, urinalysis, AE monitoring,        serum pregnancy test for women of child-bearing potential    -   Analytical Method: Fospropofol and propofol will be analyzed in        plasma samples using a validated method. Additional plasma        samples may be drawn and stored for possible future bioanalysis        of other analytes.    -   Pharmacokinetic Parameters: The following pharmacokinetic        parameters will be calculated for both fospropofol and propofol        plasma concentrations: AUC_(0-t), AUC_(0-inf), C_(max), Residual        area, T_(max), T_(1/2 el), K_(el), Cl/F, Vd/F, and Vd/F/kg.    -   Statistical Analyses: Statistical analyses will be performed        with the safety, tolerability, efficacy, and PK data

Laboratory Assessments—Example A12

Hematology: Hematology will be drawn at screening, at clinic check-in,and at the follow-up (final) visit. Hematology will include completeblood count with differential, hemoglobin, and hematocrit.

Chemistry: Blood chemistry will be drawn at screening, at cliniccheck-in, and at the follow-up (final) visit. Blood chemistry willinclude albumin, alkaline phosphatase, aspartate aminotransferase,alanine aminotransferase, urea, calcium, chloride, glucose, phosphorus,potassium, creatinine, sodium, total bilirubin, and total protein.

Serology: Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIVantigen and antibody detection will be drawn at screening.

Urinalysis: Urine for Urinalysis will be taken at screening, at cliniccheck-in, and at the follow-up (final) visit. Urinalysis will includemacroscopic examination, pH, specific gravity, protein, glucose,ketones, bilirubin, occult blood, nitrite, urobilinogen, and leukocytes.Unless otherwise specified, microscopic examination will be performed onabnormal findings.

Drug, Cotinine, and Alcohol Screen: A urine drug screen (amphetamines,methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol,cocaine, opiates, PCP, MDMA, methadone), a urine cotinine test, and analcohol breath test will be performed at screening and at cliniccheck-in.

Pregnancy Tests: For women of child bearing potential: A serum pregnancytest will be performed at screening. A urine pregnancy test will beperformed at clinic check-in. A serum pregnancy test will be performedat the follow-up (final) visit, and at early termination, whereapplicable.

Example A13

Safety-tolerability, pharmacokinetics, and efficacy of single pulsedascending oral doses of Fospropofol Disodium administered to adult malesand females for the acute treatment of moderate to severe migraineheadache.

-   -   Study Drug: Fospropofol Disodium    -   Study Phase and Type: Phase 2a—Single Pulsed Ascending Dose        (SAD) in adults with migraine    -   Study Design: Multi-center, Phase 2a, placebo controlled,        modified double-blind, Single Pulsed Ascending Dose,        safety-tolerability, pharmacokinetic (PK), and efficacy study of        Fospropofol Disodium in adult males and females for the acute        treatment of moderate to severe migraine headache. The study is        characterized as modified double-blind because treatment        assignment will be unblinded for review of safety-tolerability,        propofol PK, and efficacy following each dosing stage.        -   The study will evaluate 3 ascending dose levels of a pulsed            dose (in 3 stages) with dose levels to be selected on the            basis of the prior Phase 2a SAD study in subjects with acute            migraine (Study Fospropofol Disodium). Separate cohorts of            12-500 subjects will be randomized to receive a fixed dose            (all subjects) followed by ascending pulsed doses of            Fospropofol Disodium or matching placebo (9-375 subjects to            receive a pulsed dose of Fospropofol Disodium and 3-125            subjects to receive a pulsed dose of placebo at each dose            level). During each dosing stage subjects and investigators            will be blinded to the treatment assignment.    -   Subjects: Up to 500 adult males and females ≥18 and ≤55 years of        age with a body mass index (BMI) within 18.0-35.0 kg/m²        inclusive and body weight >50 kg. Females of childbearing        potential must be using reliable contraception or totally        abstain from intercourse.        -   Three separate cohorts of up to 160 subjects will receive a            fixed dose of Fospropofol Disodium followed by a second            “pulsed” dose of Fospropofol Disodium 30 minutes later (up            to 120 subjects) or a second “pulsed” dose of placebo 30            minutes (up to 40 subjects) at each of three ascending dose            levels. Each cohort of up to 160 to be balanced on gender            1:1 or 1.3:1 with no fewer than 50% females. Subjects who            withdraw or are withdrawn from the study after dosing, for            reasons other than safety and tolerability, may be replaced            after consultation with the Safety Review Committee.    -   Screening Procedures: Demographic data, medical and medication        histories including drug allergies, physical examination, body        measurements, electrocardiogram (ECG), vital signs (blood        pressure [BP], heart rate [HR], respiratory rate [RR], pulse        oximetry [PO], and oral temperature [OT]), hematology, blood        chemistry, human immunodeficiency virus (HIV), hepatitis B and C        tests, urinalysis, urine drug screen, alcohol breath test, urine        cotinine test, Serum pregnancy test (women of child-bearing        potential). Screening to occur within 30 days of clinic        admission. [Subjects who do not present with a qualifying        headache within 30 days of screening may have a second screening        visit within 45 days of the first screening at the discretion of        the investigator. Second screening visit may be abbreviated to        updated history and serum pregnancy test for women of        childbearing potential. A subject who does not present with a        qualifying headache within 30 days of the second screening will        be classified as a screening failure.]        -   Migraine History: Confirm migraine diagnosis according to            ICHD criteria, age of onset, estimated frequency of migraine            episodes, including frequency of episodes classified as            moderate or severe, history of migraine-associated symptoms            (nausea/vomiting, photophobia, phonophobia), characteristic            features of episodes including aura (if any), nature of            pain, associated symptoms; history of headache types other            than migraine, history of medications (if any) used for            treatment of acute migraine (past and current); history of            medications (if any) used for the the purpose of migraine            prophylaxis (past and current). Identification of an            appropriate “rescue” treatment (See Rescue Treatment below)    -   Confinement clinic: in Subjects will arrive at the study clinic        during the course of a migraine headache of at least moderate        severity (in the subject's judgment). Subjects will be confined        to the study site for 1 to 2 hours before dosing and confined        until at least 9 hours following the initial dose of study drug.    -   Study Drug and Dosage Form: Fixed dose for the initial dose (all        stages) and three ascending active dose levels for the second        (pulsed) dose        -   Fospropofol Disodium to be administered as an appropriate            number of powder filled capsules, each capsule containing            200 mg of fospropofol disodium and/or 100 mg of fospropofol            disodium (Epalex Corporation, USA).        -   Placebo to be administered (second “pulsed” dose) as an            equivalent number of identical capsules containing placebo.    -   Study Drug Administration: Each cohort of up to 160 subjects        will receive the same single fixed oral dose selected from        100-3600 mg of Fospropofol Disodium (N=160) as the initial dose.        After 30 minutes, subjects will receive a second “pulsed” dose        of Fospropofol Disodium (N=up to 120) or matching placebo (N=up        to 40). The amount of the second “pulsed” dose will increase at        each stage (ascending dose design).        -   Fospropofol Disodium will be administered as capsules            containing 200 mg and/or 100 mg of fospropofol disodium            (Fospropofol Disodium) to achieve the planned dose.        -   Study drug (each of the two administrations) will be            administered with 240 mL of water at ambient temperature.            Except for water administered with study drug, no fluids            will be allowed from 1 hour before dosing until 1 hour            post-dose.        -   There will be at least 7 days between dosing of each dose            level. Following completion of each dose level,            pharmacokinetic (PK) data for propofol collected until 9            hours post-dose (where time post-dose refers to the time            interval from the initial dose), safety and tolerability            data collected until the clinic check-out (approximately 10            hours post-dose), and the efficacy data collected until 9            hours post-dose will be evaluated by a Safety Committee            before proceeding to the next dose.    -   Inclusion Criteria Male or female, non-smoker (no use of tobacco        products within 3 months prior to screening), ≥18 and ≤55 years        of age, with BMI ≥18.0 and ≤32.0 kg/m² and body weight ≥50.0 kg        Generally healthy (other than migraine) as defined by:        -   The absence of clinically significant illness and surgery            within 4 weeks prior to dosing. Subjects vomiting within 24            hours pre-dose will be carefully evaluated. Inclusion            pre-dosing is at the discretion of the center PI.        -   The absence of clinically significant history of            neurological (other than migraine), endocrine,            cardiovascular, pulmonary, hematological, immunologic,            psychiatric, gastrointestinal, renal, hepatic, and metabolic            disease.        -   The absence of clinically significant history of sleep apnea        -   Subject has at least 1 year history of migraines (with or            without aura), consistent with a diagnosis according to the            International Classification of Headache Disorder, 3rd            Edition, Beta version including the following:        -   Migraine attacks present for more than 1 year with age of            onset prior to 50 years of age        -   Migraine attacks last, 4 to 72 hours if untreated, on            average, in the 3 months prior to screening visit        -   Two to eight (2-8) moderate or severe migraine attacks per            month in the 3 months prior to the screening visit. The            migraine, for which the patient receives treatment during            the study, must have at least one of the associated            symptoms: nausea, photophobia, phonophobia, or migraine with            aura        -   Subjects on prophylactic migraine medication are permitted            to remain on therapy provided they have been on a stable            dose for at least 3 months prior to screening visit and the            dose is not expected to change during the course of the            study        -   Clinical laboratory values within the laboratory acceptable            range unless values are deemed by the PI/Sub-Investigator as            “Not Clinically Significant”.        -   Ability to comprehend the nature of the study, as assessed            by the PI/Sub-Investigator. Capable of giving written            informed consent. Able to communicate effectively with            clinic staff.        -   Availability to volunteer for the entire study duration and            willing to adhere to all protocol requirements.        -   Female subjects must agree not to be nursing at any time            during the study and until 30 days after the study follow-up            visit.        -   Female subjects must fulfill at least one of the following:        -   Be surgically sterile for a minimum of 6 months;        -   Post-menopausal for a minimum of 1 year;        -   Agree to avoid pregnancy and use medically acceptable method            of contraception from at least 30 days prior to the study            until 30 days after the study follow-up visit.        -   Medically acceptable methods of contraception include            hormonal contraception, hormonal or non-hormonal            intrauterine device, or double barrier method (simultaneous            use of male condom with intravaginally applied spermicide            and diaphragm or cervical cap). Complete abstinence alone            can be used as a method of contraception.        -   Subjects with coexisting history of headache other than            migraine are eligible provided that these headaches are            distinguishable from the subject's migraine headaches        -   No contraindication to use of fospropofol according to FDA            approved labeling        -   Concomitant medications taken for the purpose of migraine            prophylaxis are permitted provided that the dose of these            medications is stable for at least 3 months prior to            administration of study drug and estimated headache            frequency at screening meets the criterion above        -   If concomitant medications intended to reduce the frequency            of migraine are discontinued prior to the study, these            medications must be discontinued at least one month prior to            receiving study drug        -   Absence of any medical condition that, in the opinion of the            investigator or the Sponsor, may be potentially associated            with an increased risk from study drug or participation in            the study.        -   Subject must be willing to avoid the use of analgesics or            any acute migraine medication(s) for 24 hours prior to            receiving study drug.        -   Subject must be willing to forgo rescue treatment (defined            below) for 2 hours after initiation of treatment with study            drug.    -   Exclusion Criteria Subjects to whom any of the following applies        will be excluded:        -   Patient has basilar migraine or hemiplegic migraine        -   Patient is taking narcotic (opiate) medication        -   Patient uses an opiate as first line acute treatment for            migraine attacks        -   History of ergotamine, triptan, or any acute therapy intake            on ≥10 days per month on a regular basis for ≥3 months        -   History of simple analgesic intake on ≥10 days per month for            ≥3 months        -   History of use of opioid or combination medication intake or            butalbital containing analgesic greater than 5 days per            month for ≥3 months        -   Very frequent chronic tension type headaches for 15 or more            days per month (or unable to distinguish between            tension-type headaches and migraine)        -   Patient has major depression, other pain syndromes that            might interfere with study assessments, psychiatric            conditions, dementia, or significant neurological disorders            (other than migraine)        -   Any clinically significant abnormality at physical            examination, clinically significant abnormal laboratory test            results or positive serologic test for hepatitis B,            hepatitis C, or HIV found during medical screening.            (Subjects with positive serology for hepatitis C and            negative HCV RNA are eligible at the discretion of the            principal investigator.)        -   Positive urine drug screen (unless consistent with an            ongoing prescription drug as documented by the center            investigator), positive alcohol breath test, urine cotinine            test at screening or at clinic check-in        -   Positive serum pregnancy test (women of child-bearing            potential) at screening (or positive urine pregnancy test at            clinic check-in).        -   History of severe allergic reactions (e.g. anaphylactic            reactions, angioedema), hypersensitivity or idiosyncratic            reaction to fospropofol, propofol, Fospropofol Disodium            excipients or related substances.        -   Individuals having undergone any major surgery within 6            months prior to the start of the study, unless deemed            otherwise by the PI.        -   Clinically significant ECG abnormalities (e.g., QTcF>450            msec in males or >470 msec in females) or persistent (3            determinations) vital sign abnormalities at screening            (systolic blood pressure lower than 90 or over 145 mmHg,            diastolic blood pressure lower than 55 or over 95 mmHg, or            heart rate less than 50 or over 100 bpm). Vital signs to be            taken in a seated position and may be repeated up to a total            of three determinations.        -   Oxygen saturation by oximetry less than 93% at screening        -   History of significant alcohol abuse within one year prior            to screening or regular use of alcohol within six months            prior to the screening visit (more than fourteen units of            alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or            45 mL of 40% alcohol]).        -   History of significant drug abuse within one year prior to            screening or use of hard drugs (such as cocaine,            phencyclidine [PCP], crack, opioid derivatives including            heroin, and amphetamine derivatives) within 1 year prior to            screening.        -   Participation in an interventional clinical research study            involving the administration of an investigational or            marketed drug or device within 30 days prior to            administration of study drug or administration of a            biological product in the context of a clinical research            study within 90 days prior to administration of study drug.            Concomitant participation in an investigational study            involving no drug or device administration is permitted            provided obligations associated with the concomitant            participation are not expected to interfere with procedures            and obligations of the present study.        -   Any medical condition (other than migraine) requiring            ongoing, more than occasional, use of analgesic drugs.            (Occasional use of acetaminophen, aspirin, or NSAID, or            topical products without significant systemic absorption is            not an exclusion).        -   Any medical condition requiring ongoing treatment with            sedative-hypnotic drugs (e.g., benzodiazepines,            barbiturates)        -   Donation of plasma within 7 days prior to dosing. Donation            or loss of blood (excluding volume drawn at screening) of 50            mL to 499 mL of blood within 30 days, or more than 499 mL            within 56 days prior to the first dosing.        -   Hemoglobin <135 g/L for men or <120 g/L for women at            screening.        -   Intolerance to and/or difficulty with blood sampling through            venipuncture.        -   Abnormal diet patterns (for any reason) during the four            weeks preceding the study, including fasting, high protein            diets etc.        -   Employee or immediate relative of an employee of Epalex            Corporation, its affiliates or partners.    -   Study Restrictions: Analgesic drugs, e.g., opiates alone or in a        combination product from screening until the end-of-study        follow-up visit. Occasional use of acetaminophen, aspirin, or an        NSAID will be permitted; however, a subject will not be eligible        to receive study drug if he/she has taken any analgesic        (including over the counter) in the preceding 24 hours.        Analgesics (except as rescue) are not permitted from 24 hours        prior to clinic admission until the end-of-study follow-up        visit.        -   Marijuana products including THC and CBD are not permitted            from screening until the end-of-study follow-up visit.        -   Sedative-hypnotic drugs, prescription or OTC, (e.g.,            benzodiazepines, barbiturates, sleeping aids, Fiorinal) from            screening until the end-of-study follow-up visit.        -   Triptans, e.g., sumatriptan, Imitrex (except as rescue,            where applicable) are not permitted from screening until the            end-of-study follow-up visit.        -   Ergotamine or combination drugs, containing ergotamine e.g.            cafergot (except as rescue, where applicable) from screening            until the end-of-study follow-up visit.        -   Metoclopramide, e.g. Reglan (except as rescue, where            applicable) from screening until the end-of-study follow-up            visit.        -   Alcohol-based products are permitted; however, a subject            will not be eligible to receive study drug if he/she has            taken any alcohol based product in the preceding 24 hours.            Alcohol-based products are not permitted from 24 hours prior            to clinic admission until the end-of-study follow-up visit.        -   Prescription and OTC medications that are medically            necessary (except analgesics, sedative-hypnotics, and drugs            intended for treatment of acute migraine, as described            above) are permitted. The center principal investigator (PI)            will review, record, and approve at screening the            concomitant medications expected to be continued over the            course of study. In case of questions as to the suitability            of a concomitant medication, investigators are encouraged to            consult with the Sponsor.        -   For safety reasons, subjects will be required to remain            seated or semi-reclined and avoid sleeping for the first 1            hour before and 4 hours after drug administration.    -   PK Sampling Time Points: A total of 14 blood samples (for        analysis of both fospropofol and propofol) will be collected (in        each dose level or period): Pre-dose (within 10 min of dosing)        and post-dose: 5, 10, 20, 30, 45, 60, 90 minutes and 2, 3, 4, 5,        6, and 9 hours post-dose.    -   Subject Monitoring: Safety Medical surveillance and AE        monitoring:        -   Subjects will be monitored throughout the study by Clinic            staff for AEs.        -   Continuous cardiac telemetry and pulse oximetry:        -   To detect any clinically significant cardiac arrhythmia or            other abnormality at baseline (pre-dose), cardiac telemetry            will be performed for at least 30 minutes prior to dosing            and continued until approximately 9 hours post-dose to            monitor for any cardiac effects of study drug. Subjects with            any clinically significant ECG abnormality at baseline            (pre-dose) will be excluded. Pulse oximetry will be            monitored over the same time course.        -   Vital signs:        -   BP, HR, RR, and Pulse Oximetry (PO) will be recorded            pre-dose within 10 min of dosing and at approximately 5, 10,            20, 30, 45, 60, 90 2, 2.5, 3, 4, 6, and 9 hours after            dosing.        -   Level of Alertness        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) Score.            See Chernik D A, Gillings D, Laine H, et al. Validity and            reliability of the Observer's Assessment of            Alertness/Sedation Scale: study with intravenous midazolam.            J Clin Psychopharmacol 1990 August; 10(4):244-51.        -   Responsiveness Score        -   Responds readily to name spoken in normal tone 5 (alert)        -   Lethargic response to name spoken in normal tone 4        -   Responds only after name is called loudly and/or 3            repeatedly        -   Responds only after mild prodding or shaking 2        -   Responds only after painful trapezius squeeze 1        -   Does not respond to painful trapezius squeeze 0        -   Sedation (MOAA/S score) will be recorded within 10 min            pre-dose and at approximately 5 min intervals until 3 hours            after dosing, and at 15 min intervals thereafter until 9            hours post-dose provided that the subject has demonstrated            at least three consecutive MOAA/S scores of 5 immediately            prior to the the 3 hour timepoint. A subject who has not            demonstrated three consecutive MOAA/S scores of 5            immediately prior to the the 3 hour timepoint will continue            with MOAA/S assessments at 5 min intervals until he or she            demonstrates three consecutive MOAA/S scores of 5, with            MOAA/S scores recorded at 15 min interval thereafter until 9            hours post-dose. See Cohen L B. Clinical trial: a            dose-response study of fospropofol disodium for moderate            sedation during colonoscopy. 2008; Aliment Pharmacol Ther            27, 597-608.        -   12-lead ECG:        -   12-lead ECG will be performed at Clinic check-in (Day 1            before dosing) and at Clinic checkout.        -   Laboratory assessments:        -   Hematology, biochemistry, and urinalysis at clinic check-in            and at follow-up (final) visit scheduled between 48 h and 96            h after administration of study drug.        -   Alcohol breath test, urine cotinine test, and urine drug            screen at check-in.        -   For women of child-bearing potential, urine pregnancy test            at check-in; serum pregnancy test at follow-up (final) visit            scheduled between 48 h and 96 h after administration of            study drug [A serum pregnancy test will be obtained at            screening.]        -   Physical examination:        -   Complete physical exam (PE) at screening, brief PE at clinic            check-in and clinic checkout; complete PE at follow-up            (final) visit scheduled between 48 h and 96 h after            administration of study drug    -   Clinic Check-in Food will not be permitted from the time of        clinic check-in until 4 hours after the initial dosing of study        drug. Fluids will not be permitted from one hour before the        initial dose until one hour after administration of the second        (pulsed dose) of study drug (except for water (240 mL)        administered with study drug.) Water will be permitted ad lib at        all other times.        -   Abbreviated physical exam, alcohol breath test, and urine            drug screen at check-in. Urine pregnancy test (women of            child-bearing potential)        -   Record time and nature of last meal or food intake        -   Record concomitant medications and all medications taken in            the 24 hours prior to check-in.        -   Record characteristics of the presenting headache and            associated symptoms including, but not limited to the            following:        -   Characteristics of the presenting headache (i.e., throbbing,            unilateral or bilateral, aggravated by exercise,).        -   Subject's assessment of headache pain at admission to clinic            on a 4-point Likert Scale, (i.e., 0=none, 1=mild,            2=moderate, 3=severe) for the presenting headache.        -   Most bothersome associated symptom for the presenting            headache (e.g., nausea/vomiting, photophobia, phonophobia)        -   Presence of associated symptoms, nausea, vomiting,            photophobia, phonophobia (Yes/No) at clinic admission    -   Efficacy Measures: Note: Pre-dose and post—dose times are with        reference to the initial dose of study drug.        -   Subject's assessment of headache pain—4-point Likert Scale            (Severe, Moderate, Mild, No pain) to be assessed at baseline            prior to dosing (within 10 min of dosing), and post-dose at            5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6            h, 8 h, and at clinic discharge, and following discharge (by            diary) at 12, 24 h and 48 h post-dosing. Headache qualifying            for treatment with study drug must be of at least moderate            severity at baseline (pre-dose and within 10 min of dosing            study drug). Subjects will be asked to announce while in            clinic the time that no headache pain is first noted, or,            after discharge, if applicable, to record the time that no            headache pain is first noted in the patient diary. Subjects            will also be asked to announce in clinic and/or record by            patient diary after discharge from clinic any recurrence or            worsening of headache pain, and time of onset of worsening.        -   Subject's assessment of presence/absence of most bothersome            symptom (MBS)—subjects to be questioned as to presence or            absence of the most bothersome symptom associated with            presenting headache (identified at clinic admission) at the            same time points as the assessment of headache pain            [baseline prior to dosing (within 10 min of dosing), and            post-dose at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h,            3 h, 4 h, 6 h, 8 h, and at clinic discharge, and following            discharge (by diary) at 12, 24 h and 48 h post-dosing.]            Subjects will also be asked to announce while in clinic the            time that disappearance of the most bothersome symptom is            first noted, or, after discharge, if applicable, to record            the time that no headache pain is first noted in the patient            diary. Subjects will also be asked to announce in clinic            and/or record by patient diary after discharge from clinic            any recurrence of the most bothersome symptom, and time of            onset of recurrence.        -   Subject assessment of presence/absence of            migraine-associated symptoms (other than MBS):            nausea/vomiting, photophobia, and/or phonophobia at baseline            (within 15 min of dosing), and post-dose at 5 min, 15 min,            30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and at            clinic discharge, and following discharge (by diary) at 12,            24 h and 48 h post-dosing. Subjects will also be asked to            announce while in clinic the time that disappearance of            migraine-associated symptoms is first noted, or, after            discharge, if applicable, to record the time that            disappearance of the associated symptom is first noted in            the patient diary. Subjects will also be asked to announce            in clinic and/or record by patient diary after discharge            from clinic any recurrence of a migraine-associated symptom,            and time of onset of recurrence.        -   While in clinic subjects will be instructed to report any            adverse events directly to the investigators or clinic            staff. Subjects will be instructed to record in the patient            diary any adverse events emerging following discharge. All            subjects will have telephone access to the investigator or            investigator staff to report any urgent concerns in the            course of the study.    -   Rescue Treatment Rescue treatment (acute treatment for migraine        pain) may be administered at any time at the investigator's        discretion. Subjects and investigators will be encouraged to        avoid administration of rescue treatment earlier than 2 hours        after initial administration of study drug. Rescue treatment may        include an analgesic and/or acute migraine medication(s).        Selection of rescue for each subject may be guided by history of        treatment effective for the subject in the past. In general, the        investigator and subject will have agreed on the appropriate        rescue therapy for the subject at screening. In identifying an        appropriate rescue therapy, the additive cardiorespiratory        effects of narcotic analgesics and sedative hypnotic agents when        administered concomitantly with fospropofol should be        considered.    -   Clinic Check-out: The following procedures will be carried out        at clinic check-out: physical examination, vital signs, 12-lead        ECG, oral temperature, AE monitoring. Distribute diary for        subjects to record and grade any ongoing headache pain, and any        ongoing migraine-associated symptoms (present/absent), and/or        any recurrence or worsening of pain or migraine-associated        symptoms. Schedule follow-up visit.    -   Follow-up Visit/End of Study Participation The following        procedures will be carried out at a follow-up end of study visit        to be scheduled 48 to 96 hours after administration of study        drug: hematology, blood chemistry, urinalysis, AE monitoring,        serum pregnancy test for women of child-bearing potential    -   Analytical Method: Fospropofol and propofol will be analyzed in        plasma samples using a validated method. Additional plasma        samples may be drawn and stored for possible future bioanalysis        of other analytes.    -   Pharmacokinetic Parameters: The following pharmacokinetic        parameters will be calculated for both fospropofol and propofol        plasma concentrations: AUC_(0-t), AUC_(0-inf), C_(max), Residual        area, T_(max), T_(1/2 el), K_(el), Cl/F, Vd/F, and Vd/F/kg.    -   Statistical Analyses: Statistical analyses will be performed        with the safety, tolerability, efficacy, and PK data

Laboratory Assessments—Example A13

Hematology: Hematology will be drawn at screening, at clinic check-in,and at the follow-up (final) visit. Hematology will include completeblood count with differential, hemoglobin, and hematocrit.

Chemistry: Blood chemistry will be drawn at screening, at cliniccheck-in, and at the follow-up (final) visit. Blood chemistry willinclude albumin, alkaline phosphatase, aspartate aminotransferase,alanine aminotransferase, urea, calcium, chloride, glucose, phosphorus,potassium, creatinine, sodium, total bilirubin, and total protein.

Serology: Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIVantigen and antibody detection will be drawn at screening.

Urinalysis: Urine for Urinalysis will be taken at screening, at cliniccheck-in, and at the follow-up (final) visit. Urinalysis will includemacroscopic examination, pH, specific gravity, protein, glucose,ketones, bilirubin, occult blood, nitrite, urobilinogen, and leukocytes.Unless otherwise specified, microscopic examination will be performed onabnormal findings.

Drug, Cotinine, and Alcohol Screen: A urine drug screen (amphetamines,methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol,cocaine, opiates, PCP, MDMA, methadone), a urine cotinine test, and analcohol breath test will be performed at screening and at cliniccheck-in.

Pregnancy Tests: For women of child bearing potential: A serum pregnancytest will be performed at screening. A urine pregnancy test will beperformed at clinic check-in. A serum pregnancy test will be performedat the follow-up (final) visit, and at early termination, whereapplicable.

Example A14

Open-label exploratory study to describe the pharmacokinetics,safety-tolerability, and clinical outcome following a single oral doseof fospropofol disodium administered to adult women and men experiencingmoderate to severe migraine headache.

-   -   Study Drug: Fospropofol Disodium    -   Study Phase and Type: Phase 1b—Open-label exploratory        single-dose administration to adults with moderate to severe        migraine headache    -   Study Design: Phase 1b, multi-center, open-label, single-dose,        exploratory study to describe PK, safety-tolerability, and        clinical outcome following a single oral dose of fospropofol        disodium administered to adult women and men experiencing        moderate to severe migraine headache.        -   The study is intended to evaluate one dose level (the            maximum well-tolerated dose to be selected on the basis of            the prior Phase 1 healthy volunteer study).    -   Subjects: Up to 150 subjects with a diagnosis of episodic        migraine will be enrolled. An interim analysis including PK,        safety-tolerability, clinical outcome data will be carried out        after completion of 50 subjects. Following the interim analysis,        the administered dose may be modified, including but not limited        to a change in the dosing regimen up or down or using a divided        dose (2 administrations separated in time).        -   The study will enroll adult women and men ≥18 and ≤55 years            of age with a body mass index (BMI) within 18.0-29.9 kg/m²            inclusive, and body weight >50 kg. Women of childbearing            potential must be using reliable contraception or totally            abstain from intercourse.        -   The overall study population enrolled must comprise at least            50% women.        -   This is a single-dose study. Subjects who withdraw or are            withdrawn from the study after dosing will not be replaced.    -   Screening Procedures: Demographic data, medical and medication        histories including drug allergies, physical examination, body        measurements, electrocardiogram (ECG), vital signs (blood        pressure [BP], heart rate [HR], respiratory rate [RR], pulse        oximetry [PO], and oral temperature [OT]), hematology, blood        chemistry, human immunodeficiency virus (HIV), hepatitis B and C        tests, urinalysis, urine drug screen, alcohol breath test, urine        cotinine test, Serum pregnancy test (women of child-bearing        potential). Screening to occur within 30 days of clinic        admission. [Subjects who do not present with a qualifying        headache within 30 days of screening may have a second screening        visit within 45 days of the first screening at the discretion of        the investigator. Second screening visit may be abbreviated to        updated history and serum pregnancy test for women of        childbearing potential. A subject who does not present with a        qualifying headache within 75 days of the first screening will        be classified as a screening failure.]        -   Migraine History: Confirm migraine diagnosis according to            ICHD criteria; age of onset, estimated frequency of migraine            episodes, including frequency of episodes classified as            moderate or severe, history of migraine-associated symptoms            (nausea/vomiting, photophobia, phonophobia), characteristic            features of episodes including aura (if any), nature of            pain, associated symptoms; history of headache types other            than migraine, history of medications (if any) used for            treatment of acute migraine (past and current); history of            medications (if any) used for the the purpose of migraine            prophylaxis (past and current). Identification of an            appropriate “rescue” treatment (See Rescue Treatment below)        -   Note that potential subjects on concomitant drugs for            migraine prophylaxis are excluded. A list of concomitant            medications requiring exclusion will be provided. Subjects            maintained on a continuing regimen of a drug intended for            migraine prophylaxis will not be eligible. Subjects            maintained on a continuing regimen of a drug prescribed for            a purpose other than migraine prophylaxis but with a            potential prophylactic effect on migraine, e.g., beta            blockers, tricyclic antidepressants will not be eligible.            Subjects in these categories may be enrolled if the            disqualifying drug is discontinued at least one month before            enrolment and the subject meets all other eligibility            criteria (e.g. headache frequency, etc., at the time of            enrolment    -   Confinement clinic: in Subjects will arrive at the study clinic        during the course of a migraine headache. To qualify for        treatment with study drug, headache must be of at least moderate        severity (in the subject's judgment) at the time of treatment.        Subjects will be confined to the study site for up to 2 hours        before dosing and confined until at least 9 hours following a        single dose of study drug.    -   Study Drug Dosage Form: and One dose level.        -   Fospropofol disodium to be administered as an appropriate            number of powder-filled capsules, each capsule containing            200 mg of fospropofol disodium (Epalex Corporation, USA).    -   Study Drug Administration: Each subject will receive a single        oral dose of Fospropofol disodium at a single dose level        selected from within the range 200 mg to 3200 mg. Fospropofol        disodium will be administered as an appropriate number of        capsules containing 200 mg of fospropofol disodium.        -   Subjects will receive a single dose of fospropofol disodium            administered as the appropriate number of capsules            containing 200 mg of fospropofol disodium.        -   The dose of fospropofol disodium will be reduced if there            are safety concerns or evidence of clinically significant            tolerability issues. In no case will the total dose to a            subject exceed the highest dose level specified in the            protocol.        -   Study drug will be administered with 240 mL of water at            ambient temperature. Except for water administered with            study drug, no fluids will be allowed from 30 min before            dosing until 1 hour post-dose.    -   Inclusion Criteria Male or female, non-smoker (no use of tobacco        products within 3 months prior to screening), ≥18 and ≤55 years        of age, with BMI≥18.0 and ≤29.9.0 kg/m² and body weight ≥50.0 kg        -   Generally healthy (other than migraine) as defined by:        -   The absence of clinically significant illness and surgery            within 4 weeks prior to dosing. Subjects vomiting within 24            hours pre-dose will be carefully evaluated. Inclusion            pre-dosing is at the discretion of the center PI.        -   The absence of clinically significant history of            neurological (other than migraine), endocrine,            cardiovascular, pulmonary, hematological, immunologic,            psychiatric, gastrointestinal, renal, hepatic, and metabolic            disease.        -   The absence of clinically significant history of sleep apnea        -   Subject has at least a one-year history of migraine (with or            without aura), consistent with a diagnosis according to the            International Classification of Headache Disorder, 3rd            Edition, including the following:        -   Migraine attacks present for more than 1 year with age of            onset prior to 50 years of age        -   Migraine attacks last, 4 to 72 hours if untreated, on            average, in the 3 months prior to screening visit        -   Two to eight (2-8) moderate or severe migraine attacks per            month in the 3 months prior to the screening visit. The            migraine, for which the patient receives treatment during            the study, must have at least one of the associated            symptoms: nausea, photophobia, phonophobia, or migraine with            aura        -   Subjects on prophylactic migraine medication are not            eligible.        -   Subjects maintained on a continuing regimen of a drug            prescribed for a purpose other than migraine prophylaxis but            with a potential prophylactic effect on migraine, e.g., beta            blockers, tricyclic antidepressants will not be eligible. (A            list of these drugs will be provided). Subjects in these            categories may be enrolled if the disqualifying drug is            discontinued at least one month before enrolment and the            subject meets all other eligibility criteria (e.g. headache            frequency, etc., at the time of enrolment.)        -   Clinical laboratory values within the laboratory acceptable            range unless values are deemed by the PI/Sub-Investigator as            “Not Clinically Significant”.        -   Ability to comprehend the nature of the study, as assessed            by the PI/Sub-Investigator. Capable of giving written            informed consent. Able to communicate effectively with            clinic staff.        -   Availability to volunteer for the entire study duration and            willing to adhere to all protocol requirements.        -   Female subjects must agree not to be nursing at any time            during the study and until 30 days after the study follow-up            visit.        -   Female subjects must fulfill at least one of the following:        -   Be surgically sterile for a minimum of 6 months;        -   Post-menopausal for a minimum of 1 year;        -   Agree to avoid pregnancy and use medically acceptable method            of contraception from at least 30 days prior to            administration of study drug until 30 days after the study            follow-up visit.        -   Medically acceptable methods of contraception include            hormonal contraception, hormonal or non-hormonal            intrauterine device, or double barrier method (simultaneous            use of male condom with intravaginally applied spermicide            and diaphragm or cervical cap). Complete abstinence alone            can be used as a method of contraception.        -   Subjects with coexisting history of headache other than            migraine are eligible provided that these headaches are            distinguishable from the subject's migraine headaches        -   No contraindication to use of fospropofol according to FDA            approved labeling        -   If concomitant medications intended to reduce the frequency            of migraine are discontinued prior to the study, these            medications must be discontinued at least one month prior to            receiving study drug        -   Absence of any medical condition that, in the opinion of the            investigator or the Sponsor, may be potentially associated            with an increased risk from study drug or participation in            the study.        -   Subject must be willing to avoid the use of analgesics or            any acute migraine medication(s) for 24 hours prior to            receiving study drug.        -   Subject must be willing to forgo rescue treatment (defined            below) for at least 2 hours after initiation of treatment            with study drug.    -   Exclusion Criteria Subjects to whom any of the following applies        will be excluded:        -   Patient has basilar migraine or hemiplegic migraine        -   Patient is taking narcotic (opiate) medication        -   Patient uses an opiate as first line acute treatment for            migraine attacks        -   History of ergotamine, triptan, or any acute therapy intake            on ≥10 days per month on a regular basis for ≥3 months        -   History of simple analgesic intake on ≥10 days per month for            ≥3 months        -   History of use of opioid or combination medication intake or            butalbital containing analgesic greater than 5 days per            month for ≥3 months        -   Very frequent chronic tension type headaches for 15 or more            days per month (or unable to distinguish between            tension-type headaches and migraine)        -   Patient has major depression, other pain syndromes that            might interfere with study assessments, psychiatric            conditions, dementia, or significant neurological disorders            (other than migraine)        -   Any clinically significant abnormality at physical            examination, clinically significant abnormal laboratory test            results or positive serologic test for hepatitis B,            hepatitis C, or HIV found during medical screening.            (Subjects with positive serology for hepatitis C and            negative HCV RNA are eligible at the discretion of the            principal investigator.)        -   Positive urine drug screen (unless consistent with an            ongoing prescription drug as documented by the center            investigator), positive alcohol breath test, urine cotinine            test at screening or at clinic check-in        -   Positive serum pregnancy test (women of child-bearing            potential) at screening (or positive urine pregnancy test at            clinic check-in).        -   History of severe allergic reactions (e.g. anaphylactic            reactions, angioedema), hypersensitivity or idiosyncratic            reaction to fospropofol, propofol, fospropofol disodium            excipients or related substances.        -   Individuals having undergone any major surgery within 6            months prior to the start of the study, unless deemed            otherwise by the PI.        -   Clinically significant ECG abnormalities (e.g., QTcF>450            msec in males or >470 msec in females) or persistent (3            determinations) vital sign abnormalities at screening            (systolic blood pressure lower than 90 or over 145 mmHg,            diastolic blood pressure lower than 55 or over 95 mmHg, or            heart rate less than 50 or over 100 bpm). Vital signs to be            taken in a seated position and may be repeated up to a total            of three determinations.        -   Oxygen saturation by oximetry less than 93% at screening        -   History of significant alcohol abuse within one year prior            to screening or regular use of alcohol within six months            prior to the screening visit (more than fourteen units of            alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or            45 mL of 40% alcohol]).        -   History of significant drug abuse within one year prior to            screening or use of hard drugs (such as cocaine,            phencyclidine [PCP], crack, opioid derivatives including            heroin, and amphetamine derivatives) within 1 year prior to            screening.        -   Participation in an interventional clinical research study            involving the administration of an investigational or            marketed drug or device within 30 days prior to            administration of study drug or administration of a            biological product in the context of a clinical research            study within 90 days prior to administration of study drug.            Concomitant participation in an investigational study            involving no drug or device administration is permitted            provided obligations associated with the concomitant            participation are not expected to interfere with procedures            and obligations of the present study.        -   Any medical condition (other than migraine) requiring            ongoing, more than occasional, use of analgesic drugs.            (Occasional use of acetaminophen, aspirin, or NSAID, or            topical products without significant systemic absorption is            not an exclusion).        -   Any medical condition requiring ongoing treatment with            sedative-hypnotic drugs (e.g., benzodiazepines,            barbiturates)        -   Donation of plasma within 7 days prior to dosing. Donation            or loss of blood (excluding volume drawn at screening) of 50            mL to 499 mL of blood within 30 days, or more than 499 mL            within 56 days prior to the first dosing.        -   Hemoglobin <135 g/L for men or <120 g/L for women at            screening.        -   Intolerance to and/or difficulty with blood sampling through            venipuncture.        -   Abnormal diet patters (for any reason) during the four weeks            preceding the study, including fasting, high protein diets            etc.        -   Employee or immediate relative of an employee of Epalex            Corporation, its affiliates or partners    -   Study Restrictions: Subjects will be asked to refrain from using        products that may potentially affect their safety, the PK        profile of the study drug, and/or assessments of clinical        outcome. Main study restrictions include the following:        -   Occasional use of analgesic drugs, e.g., opiates alone or in            a combination product, acetaminophen, aspirin, or an NSAID            will be permitted; however, a subject will not be eligible            to receive study drug if he/she has taken any analgesic            (including over the counter) in the preceding 24 hours.            Analgesics (except as rescue) are not permitted from 24            hours prior to clinic admission until the end-of-study            follow-up visit.        -   Marijuana products including THC and CBD are not permitted            from screening until the end-of-study follow-up visit.        -   Sedative-hypnotic drugs, prescription or OTC, (e.g.,            benzodiazepines, barbiturates, sleeping aids, Fiorinal) from            screening until the end-of-study follow-up visit.        -   Use of triptans, e.g., sumatriptan, Imitrex is permitted.        -   However, a subject will not be eligible to receive study            drug if he/she has taken any triptan in the preceding 24            hours. Triptans (except as rescue) are not permitted from 24            hours prior to clinic admission until the end-of-study            follow-up visit.        -   Ergotamine or combination drugs, containing ergotamine e.g.            cafergot are permitted. However, a subject will not be            eligible to receive study drug if he/she has taken any drug            containing ergotamine in the preceding 24 hours. Ergotamine            or combination drugs containing ergotamine (except as            rescue) are not permitted from 24 hours prior to clinic            admission until the end-of-study follow-up visit.        -   Metoclopramide, e.g. Reglan is permitted. However, a subject            will not be eligible to receive study drug if he/she has            taken metoclopramide, or any drug containing metoclopramide            in the preceding 24 hours.        -   Alcohol-based products are permitted; however, a subject            will not be eligible to receive study drug if he/she has            taken any alcohol-based product in the preceding 24 hours.            Alcohol-based products are not permitted from 24 hours prior            to clinic admission until the end-of-study follow-up visit.        -   Prescription and OTC medications that are medically            necessary (except sedative-hypnotics) are permitted on a            case-by-case basis. The center principal investigator (PI)            will review, record, and approve at screening the            concomitant medications expected to be continued over the            course of study. In case of questions as to the suitability            of a concomitant medication, investigators are encouraged to            consult with the Sponsor.        -   For safety reasons, subjects will be required to remain            seated or semi-reclined for the first 1 hour before and 4            hours after administration of study drug. Subjects may            ambulate to the rest room at the discretion of the            investigator, but must be accompanied by study staff while            walking to and from the rest room. Subjects will be            permitted to sleep ad lib until 4 hours after administration            except for the 2 hour assessments of headache pain and            associated migraine symptoms. The clinic staff should            attempt to record these assessments in all subjects.    -   PK Sampling Time Points: A total of 14 blood samples (for        analysis of both fospropofol and propofol) will be collected (in        each dose level or period): Pre-dose (within 10 min of dosing)        and post-dose: 5, 10, 20, 30, 45, 60, 90 minutes and 2, 3, 4, 5,        6, and 9 hours post-dose.    -   Subject Safety Monitoring: Medical surveillance and AE        monitoring: Subjects will be monitored throughout the study by        Clinic staff for AEs.        -   Continuous pulse oximetry: Pulse oximetry will be monitored            for at least 30 minutes prior to dosing and continued until            approximately 9 hours post-dose to monitor oxygen            saturation.        -   Vital signs:        -   BP, HR, RR, and Pulse Oximetry (PO) will be recorded            pre-dose within 10 min of dosing and at approximately 5, 10,            20, 30, 45, 60, 90 2, 2.5, 3, 4, 6, and 9 hours after            dosing.        -   Level of Alertness        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) Score.            See Chemik D A, Gillings D, Laine H, et al. Validity and            reliability of the Observer's Assessment of            Alertness/Sedation Scale: study with intravenous midazolam.            J Clin Psychopharmacol 1990 August; 10(4):244-51.        -   Responsiveness Score        -   Responds readily to name spoken in normal tone 5 (alert)        -   Lethargic response to name spoken in normal tone 4        -   Responds only after name is called loudly and/or 3            repeatedly        -   Responds only after mild prodding or shaking 2        -   Responds only after painful trapezius squeeze 1        -   Does not respond to painful trapezius squeeze 0        -   Sedation (MOAA/S score) will be recorded within 30 min            pre-dose and at approximately 15 min intervals until 4 hours            after dosing, and at 30 min intervals thereafter until 9            hours post-dose provided that the subject has demonstrated            at least three consecutive MOAA/S scores of 5 immediately            prior to the the 4 hour timepoint. A subject who has not            demonstrated three consecutive MOAA/S scores of 5            immediately prior to the the 4 hour timepoint will continue            with MOAA/S assessments at 15 min intervals until he or she            demonstrates three consecutive MOAA/S scores of 5, with            MOAA/S scores recorded at 30 min intervals thereafter until            9 hours post-dose. See Cohen L B. Clinical trial: a            dose-response study of fospropofol disodium for moderate            sedation during colonoscopy. 2008; Aliment Pharmacol Ther            27, 597-608.        -   12-lead ECG:        -   12-lead ECG will be performed at Clinic check-in (Day 1,            before dosing) and at Clinic checkout.        -   Laboratory assessments:        -   Hematology, biochemistry, and urinalysis at clinic check-in            and at the follow-up (final) visit to be scheduled between            48 h and 96 h after administration of study drug.        -   Alcohol breath test, urine cotinine test, and urine drug            screen at check-in.        -   For women of child-bearing potential, urine pregnancy test            at check-in; serum pregnancy test at follow-up (final) visit            scheduled between 48 h and 96 h after administration of            study drug [A serum pregnancy test will be obtained at            screening.]        -   Physical examination:        -   Complete physical exam (PE) at screening, brief PE at clinic            check-in and clinic checkout; complete PE at follow-up            (final) visit scheduled between 48 h and 96 h after            administration of study drug.    -   Clinic Check-in Food will not be permitted from the time of        clinic check-in until 4 hours after dosing of study drug. Fluids        will not be permitted from 30 min before until one hour after        administration of study drug (except for water (240 mL)        administered with study drug.) Water will be permitted ad lib at        all other times.        -   Abbreviated physical exam, alcohol breath test, and urine            drug screen at check-in. Urine pregnancy test (women of            child-bearing potential).        -   Record time and nature of last meal or food intake        -   Record concomitant medications and all medications taken in            the 24 hours prior to check-in.        -   Record characteristics of the presenting headache and            associated symptoms including, but not limited to the            following:        -   Characteristics of the presenting headache (i.e., throbbing,            unilateral or bilateral, aggravated by exercise,).        -   Subject's assessment of headache pain at admission to clinic            on a 4-point Likert Scale, (i.e., 0=none, 1=mild,            2=moderate, 3=severe) for the presenting headache.        -   Most bothersome associated symptom for the presenting            headache (e.g., nausea/vomiting, photophobia, phonophobia)            Presence of associated symptoms, nausea, vomiting,            photophobia, phonophobia (Yes/No) at clinic admission.    -   Clinical Outcome Measures: Subject's assessment of headache        pain—4-point Likert Scale (Severe, Moderate, Mild, No pain) to        be assessed at baseline prior to dosing (within 10 min of        dosing), and post-dose at 5 min, 15 min, 30 min, 45 min, 1 h,        1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and at clinic discharge, and        following discharge (by telephone interviews) at 12, 24 h and 48        h post-dosing. Headache qualifying for treatment with study drug        must be of at least moderate severity at baseline (pre-dose and        within 10 min of dosing study drug). Subjects will be asked to        announce while in clinic the time that no headache pain is first        noted, or, after discharge, if applicable, to report the time        that no headache pain is first noted in the patient diary.        Subjects will also be asked to announce in clinic and/or report        at phone interviews after discharge from clinic any recurrence        or worsening of headache pain, and time of onset of worsening.        -   Subject's assessment of presence/absence of most bothersome            symptom (MBS)—subjects to be questioned as to presence or            absence of the most bothersome symptom associated with            presenting headache (identified at clinic admission) at the            same time points as the assessment of headache pain            [baseline prior to dosing (within 10 min of dosing), and            post-dose at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h,            3 h, 4 h, 6 h, 8 h, and at clinic discharge, and following            discharge (by telephone interviews) at 12, 24 h and 48 h            post-dosing.] Subjects will also be asked to announce while            in clinic the time that disappearance of the most bothersome            symptom is first noted, or, after discharge, if applicable,            to report the time that no headache pain is first noted at            the telephone interviews. Subjects will also be asked to            announce in clinic and/or report at the telephone interviews            after discharge from clinic any recurrence of the most            bothersome symptom, and time of onset of recurrence.        -   Subject assessment of presence/absence of            migraine-associated symptoms (other than MBS):            nausea/vomiting, photophobia, and/or phonophobia at baseline            (within 15 min of dosing), and post-dose at 5 min, 15 min.            30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and at            clinic discharge, and following discharge (by diary) at 12,            24 h and 48 h post-dosing. Subjects will also be asked to            announce while in clinic the time that disappearance of            migraine-associated symptoms is first noted, or, after            discharge, if applicable, to report at telephone interviews            the time that disappearance of the associated symptom is            first noted. Subjects will also be asked to announce in            clinic and/or report by telephone interviews after discharge            from clinic any recurrence of a migraine-associated symptom,            and time of onset of recurrence.        -   While in clinic subjects will be instructed to report any            adverse events directly to the investigators or clinic            staff. Subjects will be instructed to report at telephone            interviews any adverse events emerging following discharge.            All subjects will have telephone access to the investigator            or investigator staff to report any urgent concerns in the            course of the study.    -   Rescue Treatment Rescue treatment (acute treatment for migraine        pain) may be administered at any time at the investigator's        discretion. Subjects and investigators will be encouraged to        avoid administration of rescue treatment earlier than 2 hours        after administration of study drug. Rescue treatment may include        an analgesic and/or acute migraine medication(s). Selection of        rescue for each subject may be guided by history of treatment        effective for the subject in the past. In general, the        investigator and subject will have agreed on the appropriate        rescue therapy for the subject at screening. In identifying an        appropriate rescue therapy, the additive cardiorespiratory        effects of narcotic analgesics and sedative hypnotic agents when        administered concomitantly with fospropofol should be        considered.    -   Clinic Check-out: The following procedures will be carried out        at clinic check-out: physical examination, vital signs, 12-lead        ECG, oral temperature, AE monitoring. Arrange telephone        interviews for subjects to report and grade any ongoing headache        pain, and any ongoing migraine-associated symptoms        (present/absent), and/or any recurrence or worsening of pain or        migraine-associated symptoms. Schedule follow-up visit.    -   Follow-up Visit/End of Study Participation The following        procedures will be carried out at a follow-up end of study visit        to be scheduled 48 to 96 hours after administration of study        drug: hematology, blood chemistry, urinalysis, AE monitoring,        serum pregnancy test for women of child-bearing potential.    -   Analytical Method: Fospropofol and propofol will be analyzed in        plasma samples using a validated method. Additional plasma        samples may be drawn and stored for possible future bioanalysis        of other analytes.    -   Pharmacokinetic Parameters: The following pharmacokinetic        parameters will be calculated for both fospropofol and propofol        plasma concentrations: AUC_(0-t), AUC_(0-inf), C_(max), Residual        area, T_(max), T_(1/2 el), K_(el), Cl/F, Vd/F, and Vd/F/kg.    -   Statistical Analyses: Descriptive analyses will be performed        with the PK, safety, tolerability, and clinical outcome data at        the interim analysis (N=50 completed subjects) and at end of        study.

Laboratory Assessments—Example A14

Hematology: Hematology will be drawn at screening, at clinic check-in,and at the follow-up (final) visit. Hematology will include completeblood count with differential, hemoglobin, and hematocrit.

Chemistry: Blood chemistry will be drawn at screening, at cliniccheck-in, and at the follow-up (final) visit. Blood chemistry willinclude albumin, alkaline phosphatase, aspartate aminotransferase,alanine aminotransferase, urea, calcium, chloride, glucose, phosphorus,potassium, creatinine, sodium, total bilirubin, and total protein.

Serology: Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIVantigen and antibody detection will be drawn at screening.

Urinalysis: Urine for Urinalysis will be taken at screening, at cliniccheck-in, and at the follow-up (final) visit. Urinalysis will includemacroscopic examination, pH, specific gravity, protein, glucose,ketones, bilirubin, occult blood, nitrite, urobilinogen, and leukocytes.Unless otherwise specified, microscopic examination will be performed onabnormal findings.

Drug, Cotinine, and Alcohol Screen: A urine drug screen (amphetamines,methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol,cocaine, opiates, PCP, MDMA, methadone), a urine cotinine test, and analcohol breath test will be performed at screening and at cliniccheck-in.

Pregnancy Tests: For women of child bearing potential: A serum pregnancytest will be performed at screening. A urine pregnancy test will beperformed at clinic check-in. A serum pregnancy test will be performedat the follow-up (final) visit, and at early termination, whereapplicable.

Example A15—Animal Studies

Study No. 15-1

The purpose of Study No. 15-1 (non-GLP) was to determine the maximumtolerated dose (MTD) of fospropofol when administered by oral gavage toSprague-Dawley rats (Phase 1) and to evaluate the potential toxicity offospropofol in Sprague-Dawley rats when administered once daily by oralgavage for 7 days (Phase 2). In addition, the toxicokinetic (TK)profiles of fospropofol and propofol were determined. Oral gavageadministration of fospropofol disodium to Sprague-Dawley rats at singlefospropofol dose levels up to 300 mg/kg or once daily for 7 consecutivedays at fospropofol dose levels of 150 and 250 mg/kg/day was welltolerated at all doses. Although one 150 mg/kg/day TK female was founddead on Day 7 at approximately 30 minutes postdose, the cause of deathwas considered related to the pharmacodynamic effects of fospropofol.Based on these results, the MTD was considered to be 250 mg/kg/day (1500mg/m²/day).

Study No. 15-2

The purpose of Study No. 15-2 (non-GLP) was to determine the MTD offospropofol when administered by oral gavage to Beagle dogs (Phase 1)and to evaluate the potential toxicity of fospropofol in Beagle dogswhen administered once daily by oral gavage for 7 days (Phase 2), aswell as to determine the TK profiles of fospropofol and propofol.Administration of fospropofol disodium by oral gavage to Beagle dogs atsingle fospropofol dose levels up to 120 mg/kg or at fospropofol doselevels of 120 and 160 mg/kg/day once daily for 7 days was tolerated atall doses with no mortality or adverse findings. Based on these results,the MTD was considered to be 160 mg/kg/day (3200 mg/m²/day).

Study No. 15-3

The purpose of Study No. 15-3 (GLP) was to determine the potentialtoxicity of fospropofol in Sprague-Dawley rats when administered oncedaily by oral gavage for 14 days. Administration of fospropofol disodiumby once daily oral gavage to Sprague-Dawley rats at fospropofol doselevels of 0, 50, 100, and 250 mg/kg/day for 14 consecutive days resultedin treatment-related mortalities at 250 mg/kg/day. The cause of deathfor the three 250 mg/kg/day group main study females found dead couldnot be determined, but was considered related to the pharmacodynamiceffects of fospropofol, based on the time of death relative to the timeof dose administration, and the clinical signs recorded before death.Clinical observations during the dosing period for these animalsincluded labored breathing, prostrate, splayed hindlimbs, uncoordinatedmovement, decreased activity, and eyes closed. There were notreatment-related gross observations or microscopic findings in any ofthese animals. Based on these results, the NOAEL was determined to be100 mg/kg/day (600 mg/m²/day). Systemic exposure to fospropofol andpropofol appeared to be dependent on sex, with greater exposure infemales. The toxicokinetic results are presented in the tables below.

Fospropofol Exposure

Following daily oral gavage administration of fospropofol disodium tomales and females at fospropofol doses of 50, 100, and 250 mg/kg/day,peak plasma concentrations (C_(max)) and area under the curve (AUC)through 6 hours after dosing (AUC_(0-6hr)) increased for fospropofol onDay 1 and Day 14 with increasing dose in a greater thandose-proportional manner. Systemic exposure (AUC_(0-6hr) values) tofospropofol did not appear to change following repeated administrationof fospropofol disodium to male and female rats) Table 15-1.

TABLE 15-1 Fospropofol Toxicokinetic Parameters on Days 1 and 14Following Daily Oral Gavage Administration of Fospropofol Disodinm (GLPStudy 15-3) Dose Treatment C_(max) T_(max) AUC_(0-6 hr) Gender (mg/kg)Day (ng/mL) (hr) (hr*ng/mL) Male 50 1 178 0.083 97.1 Male 50 14 1490.083 96.9 Male 100 1 930 0.083 386 Male 100 14 1360 0.083 370 Male 2501 8510 0.083 3720 Male 250 14 5020 0.083 2130 Female 50 1 582 0.083 166Female 50 14 341 0.25 160 Female 100 1 1630 0.083 827 Female 100 14 25600.083 1170 Female 250 1 8400 0.083 4630 Female 250 14 8440 0.083 3810Fospropofol doses of 50, 100, and 250 mg/kg were administered to maleand female Sprague-Dawley rats. Blood (plasma) was collected atalternating time points from 2 cohorts of 3 animals per sex pertreatment group at predose and approximately 0.083, 0.25, 0.5, 1, 3, and6 hours postdose.

Propofol Exposure

Following daily oral gavage administration of fospropofol disodium tomales and females, Cmax and AUC0-6 hr values for propofol increased withincreasing fospropofol dose in an approximately dose-proportional manneron Days 1 and 14. Systemic exposure (AUC_(0-6hr) values) to propofol didnot appear to change following repeated administration of fospropofoldisodium to male rats, but exposure appeared to increase followingrepeated administration of fospropofol disodium to female rats (Table15-2).

TABLE 15-2 Propofol Toxicokinetic Parameters on Days 1 and 14 FollowingDaily Oral Gavage Administration of Fospropofol Disodinm (GLP Study15-3) Dose Treatment C_(max) T_(max) AUC0-6 hr Gender (mg/kg) Day(ng/mL) (hr) (hr*ng/mL) Male 50 1 140 0.5 219 Male 50 14 301 0.25 416Male 100 1 503 0.25 821 Male 100 14 641 0.25 989 Male 250 1 1190 0.252140 Male 250 14 1430 0.29 1280 Female 50 1 404 0.25 477 Female 50 141080 0.25 1050 Female 100 1 781 0.25 1780 Female 100 14 1830 0.25 3070Female 250 1 2730 0.25 4160 Female 250 14 4440 0.5 9290 Fospropofoldoses of 50, 100, and 250 mg/kg were administered to male and femaleSprague-Dawley rats. Blood (plasma) was collected at alternating timepoints from 2 cohorts of 3 animals per sex per treatment group atpredose and approximately 0.083, 0.25, 0.5, 1, 3, and 6 hours postdose.Study No. 15-4

The purpose of Study No. 15-4 (GLP) was to determine the potentialtoxicity of fospropofol in Beagle dogs when administered once daily byoral gavage for 14 days. Administration of fospropofol disodium oncedaily by oral gavage to Beagle dogs at fospropofol dose levels of 0, 50,100, and 160 mg/kg/day for 14 consecutive days was well tolerated at alldose levels with no adverse findings. Because the treatment-relatedclinical observations (consistent with the expected transient sedativeactions of fospropofol) and effects on hematology and clinical chemistryparameters were considered nonadverse, the NOAEL was determined to be160 mg/kg/day (3200 mg/m²/day). The toxicokinetic results are presentedin the tables below.

Fospropofol Exposure

Following daily oral gavage administration of fospropofol disodium,plasma concentrations of fospropofol increased rapidly. The Tmax rangedfrom 0.0833 to 1 hour after dosing (Table 15-3). No consistent changesin Tmax with time, dose, or sex were observed. Where accuratedetermination was possible, apparent individual terminal half-livesvaried from 0.3 to 0.6 hours in males and females.

In both males and females, fospropofol Cmax and AUC_(0-6hr) increased ina manner that was less than dose proportional on Days 1 and 14, exceptin females on Day 14, where the increase was dose proportional. Amongmales, Cmax and AUC_(0-6hr) did not increase with repeat dosing, whereasamong females AUC_(0-6hr) appeared to increase with repeat dosing at the100-mg/kg and the 160-mg/kg propofol dose levels (Table 15-3). Aftersingle and repeated oral gavage administration at propofol dose levelsof 50, 100, and 160 mg/kg/day for 14 days, no clear sex differences werenoted for C_(max) or AUC_(0-6h); however, at 100 and 160 mg/kg/day onDay 14, a slight trend toward a lower exposure was observed in malescompared to females.

TABLE 15-3 ospropofol Toxicokinetic Parameters on Days 1 and 14Following Daily Oral Gavage Administration of Fospropofol Disodium (GLPStudy 15-4) Dose Treatment Cmax Tmax AUC0-6 hr Gender (mg/kg) Day(ng/mL) (hr) (hr*ng/mL) Male 50 1 5130 0.5-1 7710 Male 50 14 3300 0.5-14860 Male 100 1 9480 0.5-1 11700 Male 100 14 6340 0.25-1  6340 Male 1601 10000 0.25-1  13500 Male 160 14 6970 0.083-1  9000 Female 50 1 36800.5-1 4710 Female 50 14 3770 0.5-1 5730 Female 100 1 10100  0.25-0.511900 Female 100 14 9310 0.5-1 15100 Female 160 1 7380 0.25-1  11200Female 160 14 12700 0.25-1  16000 Fospropofol doses of 50, 100, and 160mg/kg were administered to male and female Beagle dogs. Blood (plasma)was collected from separate cohorts of 4 animals per sex per treatmentgroup at predose and approximately 0.083, 0.25, 0.5, 1, 3, and 6 hourspostdose.

Propofol Exposure

The metabolite propofol was formed with a T_(max) of 0.0833 to 1 hour inmost groups after dosing (Table 15-4). No consistent changes in Tmaxwith time, dose, or sex were observed. Where accurate determination waspossible, apparent individual terminal half-lives varied from 0.8 to 1.8hours in males and from 0.5 to 1.3 hours in females.

Following daily oral gavage administration of fospropofol disodium,propofol Cmax and AUC0-6 hr appeared to increase in both sexes in amanner that was dose proportional on Day 1 and more than doseproportional on Day 14. At the 160-mg/kg propofol dose, after 14 days ofdosing, C_(max) increased about 7-fold in males and 3-fold in femalescompared with Day 1; AUC_(0-6hr) after 14 days of dosing compared withDay 1 increased over 2-fold in males and over 5-fold in females (Table15-4). It should be noted that these observations should be interpretedwith caution due to relatively high variability of TK parameters amonganimals within the same dose group.

TABLE 15-4 Propofol Toxicokinetic Parameters on Days 1 and 14 FollowingDaily Oral Gavage Administration of Fospropofol Disodium (GLP Study15-4) Dose Treatment C_(max) T_(max) AUC0-6 hr Gender (mg/kg) Day(ng/mL) (hr) (hr*ng/mL) Male 50 1 156  1-3 211 Male 50 14 184 1 275 Male100 1 505 0.5-1 777 Male 100 14 764 0.5-1 1220 Male 160 1 399 0.0833-1  716 Male 160 14 2900 0.25-1  1970 Female 50 1 171 1 269 Female 50 14 1411 189 Female 100 1 414 0.5-1 672 Female 100 14 639 1 972 Female 160 1447 0.0833-1   637 Female 160 14 1620 0.25-1  1770 Fospropofol doses of50, 100, and 160 mg/kg were administered to male and female Beagle dogs.Blood (plasma) was collected from separate cohorts of 4 animals per sexper treatment group at predose and approximately 0.083, 0.25, 0.5, 1, 3,and 6 hours postdose.Summary of Nonclinical Toxicology of Fospropofol Disodium

Pivotal GLP 14-day repeat-dose toxicity studies with 7-day recoveryperiods were conducted in Sprague-Dawley rats (Study No. 15-3) andBeagle dogs (Study No. 15-4). In the rats, daily oral administration offospropofol disodium for 14 days at fospropofol dose levels of 0, 50,100, and 250 mg/kg/day (0, 300, 600, and 1500 mg/m²/day, respectively)resulted in 4 mortalities at the high dose level. The cause of death forthese animals was considered to be related to the known pharmacodynamiceffects of high doses of fospropofol, based on the time of deathrelative to the time of dose administration, and the clinical signsrecorded before death which included: labored breathing, prostrate,splayed hindlimbs, uncoordinated movement, decreased activity, and eyesclosed. Other treatment-related effects included reduced body weightgain at 250 mg/kg/day, and a transient increase in prothrombin time at250 mg/kg/day. There were no treatment-related histopathology findingsin any tissues, including all GIT-related tissues that were evaluated,indicating that there were no local toxicities associated with orallyadministered fospropofol disodium at fospropofol dose levels up to 250mg/kg/day (the MTD established in this species). The NOAEL wasdetermined to be 100 mg/kg/day (600 mg/m²/day) in male and femaleSprague-Dawley rats.

In Beagle dogs, daily oral administration of fospropofol disodium for 14days at fospropofol dose levels of 0, 50, 100, and 160 mg/kg/day (0,1000, 2000, and 3200 mg/m²/day, respectively) resulted in nomortalities. As in the rat, CNS-related clinical signs were observedwhich were consistent with the established pharmacodynamic effects offospropofol. There were no toxicologically significant changes in bodyweights, cardiovascular evaluations (ECGs, including QTc),ophthalmology, clinical pathology (hematology, coagulation, clinicalchemistry, and urinalysis), and absolute or relative organ weights. Nogross necropsy findings were observed at main or recovery sacrifices,and there were no treatment-related histopathological findings in anytissues, including all GIT-related tissues. As for the rat, the absenceof histopathology findings in the GIT indicated that there were no localtoxicities associated with orally administered fospropofol disodium atfospropofol dose levels up to 160 mg/kg/day in the dog (the MTDestablished in this species). The NOAEL was determined to be 160mg/kg/day (3200 mg/m²/d) in male and female Beagle dogs.

Overall, no new treatment-related adverse findings were observed in theoral fospropofol toxicology studies that would limit the use offospropofol disodium in healthy volunteer or migraine patientpopulations.

Example A16

Part 1: PK of Single Ascendin, Doses of Fospropofol Disodium (200 to2000 mg)

Part 1 of Study A16 was a double-blind, randomized, placebo-controlledstudy to investigate the safety-tolerability and PK of oraladministration of single ascending doses of fospropofol disodium tohealthy adult male and female volunteers.

Subjects were healthy adults (age 18-55 years inclusive, BMI 18-29.9kg/m²). Separate cohorts of 12 subjects each were randomized to receivefospropofol disodium at doses of 200, 400, 800, 1000, 1200, 1600, or2000 mg (n=10 per cohort) or matching placebo (n=2 per cohort).

Subjects were admitted to the clinical unit for an overnight fast(Day−1), administered study drug on Day 1, and remained in the clinicalunit until Day 2.

Fospropofol disodium was formulated as powder in an HPMC capsule, eachcapsule containing 200 mg of fospropofol disodium (weight adjusted forwater content). Placebo was administered as an appropriate number ofmatching capsules.

Blood samples were collected for analysis of fospropofol and propofol atpredose and at 5, 10, 20, 30, 45 minutes, and 1, 1.5, 2, 4, 6 and 9hours postdose (Cohorts 1-2). Based on PK results from the earlycohorts, sampling times were optimized beginning with Cohort 3 (800 mg)to predose, 5, 10, 15, 20, 25, 30, 37, and 45, minutes and 1, 2, 4, 6,and 9 hours after dosing.

The following pharmacokinetic parameters were determined for fospropofoland propofol from plasma: area under the curve from time of dosing tolast measured time point (AUC_(0-t)), area under the curve from time ofdosing extrapolated to infinity (AUC_(0-inf)), residual area, maximumplasma concentration (C_(max)), time to maximum concentration (T_(max)),t_(1/2), apparent clearance (Cl/F), and apparent volume of distribution(Vd/F).

Pharmacokinetic parameters are summarized in Table 16-1 and Table 16-2.Mean concentration vs. time plots for fospropofol and propofol by cohortare shown in FIG. 1 .

Table 16-1 and FIG. 1 indicate that the median Tmax for fospropofoloccurred at approximately 20 minutes, with fospropofol concentrationsfalling substantially (to less than 10% of C_(max)) by 2 hours afterdosing.

Table 16-2 and FIG. 1 indicate that the median Tmax for propofol wasdose-related, ranging from 30 minutes after the 200-mg dose to 45minutes after doses of 1600 or 2000 mg, with propofol concentrationsfalling substantially (to less than 25% of Cmax) by 4 hours afterdosing.

TABLE 16-1 Study A16 Part 1: PK Parameters for Fospropofol After OralAdministration of Fospropofol Disodium Dose AUC_(0-T) AUC_(0-∞) C_(max)T_(max) t_(1/2) CL/F (mg) (ng · h/mL) (ng · h/mL) (ng/mL) (h) (h) (L/h)200 856 (435) 882 (432) 1977 (758) 0.33 (0.33-0.50) 0.21 (0.05) 277(127) 400 2202 (958) 2231 (960) 4460 (1811) 0.33 (0.17-0.50) 0.24 (0.07)211 (96) 800 3288 (906) 3356 (921) 6041 (1854) 0.33 (0.24-0.50) 0.27(0.07) 254 (64) 1000 4702 (1634) 4845 (1759) 8243 (2332) 0.33(0.25-0.42) 0.29 (0.08) 229 (74) 1200 4399 (1425) 4502 (1410) 7110(1613) 0.33 (0.25-0.50) 0.34 (0.07) 288 (82) 1600 6094 (1589) 6305(6305) 10233 (2763) 0.33 (0.25-0.42) 0.35 (0.11) 270 (70) 2000 10821(3866) 10970 (3859) 17088 (5487) 0.38 (0.33-0.50) 0.37 (0.13) 204 (72)Values are means (SD), or median (range) for T_(max) n = 10 subjects ineach dose cohort.

TABLE 16-1A PK Parameters for Fospropofol After oral Administration ofFospropofol Disodium on a per mg basis Dose AUC_(0-T)/mg C_(max)/mg (mgFOSP DiNa AUC_(0-∞/mg FOSP DiNa) FOSP DiNa FOSPDiNa) (ng · h/mL)/mg (ng· h/mL)/mg (ng/mL)/mg 200 4.28 4.41 9.89 400 5.51 5.58 11.15 800 4.114.20 7.55 1000 4.70 4.85 8.24 1200 3.67 3.75 5.93 1600 3.81 3.94 6.402000 5.41 5.49 8.54

TABLE 16-2 Study A16 Part 1: PK Parameters for Propofol After OralAdministration of Fospropofol Disodium Dose AUC_(0-T) AUC_(0-∞) C_(max)T_(max) t_(1/2) CL/F (mg) (ng · h/mL) (ng · h/mL) (ng/mL) (h) (h) (L/h) 200 103.4 (34) 118 (38) 69 (44) 0.50 (0.50-1.0) 3.80 (2.75) 1889 (706) 400 276 (89) 298 (95) 201 (128) 0.50 (0.50-1.0) 2.94 (1.18) 1658 (1200) 800 551 (213) 577 (215) 362 (376) 0.62 (0.33-1.0) 1.94 (0.61) 1561(564)  1000^(a) 846 (280) 887 (286) 403 (122) 0.75 (0.40-2.0) 2.02(0.47) 1213 (311) 1200 1011 (275) 1010 (257) 641 (292) 0.62 (0.42-2.0)2.06 (0.94) 1260 (326) 1600 1475 (595) 1602 (590) 748 (331) 0.75(0.75-2.0) 2.95 (1.87) 1182 (623) 2000 2004 (627) 2253 (536) 806 (409)0.75 (0.50-2.00) 1.96 (0.46) 933 (237) Values are means (SD), or median(range) for T_(max) ^(a)n = 10 subjects in each dose cohort, except the1000-mg cohort for propofol (n = 9)

TABLE 16-1A PK Parameters for Fospropofol After Oral Administration ofFospropofol Disodium on a per mg basis Dose AUC_(0-T)/mg C_(max)/mg (mgFOSP DiNa AUC_(0-∞/mg FOSP DiNA) FOSP DiNA FOSPDiNa) (ng · h/mL)/mg (ng· h/mL)/mg (ng/mL)/mg 200 0.52 0.59 0.35 400 0.69 0.75 0.50 800 0.690.72 0.45 1000 0.85 0.89 0.40 1200 0.84 0.84 0.53 1600 0.92 1.00 0.472000 1.00 1.13 0.40

Dose proportionality assessment using the power model indicated that thePK parameters for fospropofol (AUC_(0-2h), AUC_(0-T), AUC_(0-∞), andC_(max)) were dose proportional over the dose range from 200 mg to 2000mg.

The PK parameters for propofol (AUC_(0-2h) and C_(max)) were doseproportional over the dose range from 200 mg to 2000 mg, whereasAUC_(0-T) and AUC_(0-∞) values for propofol increased with dose in aslightly greater than dose-proportional manner. Based on the powermodel, C_(max) and AUC_(0-∞) values for propofol were dose proportionalover the dose range from 200 mg to 1200 mg, whereas AUC_(0-T) valuesincreased with dose in a slightly greater than dose-proportional manner.

Within each cohort, the coefficient of variation (CV) around the meanC_(max) for propofol was greater than the CV around the mean C_(max) forfospropofol. The CV around the mean C_(max) for propofol ranged from 30%to 99% across the cohorts. Contributing to the wider variability inpropofol C_(max) was the presence of occasional “outlier” values for thepropofol C_(max) that were more than 2 standard deviations above themean for the respective dose cohort (Table 16-3).

TABLE 16-3 Study A16 Part 1: Variability in C_(max) Values for PropofolAfter Oral Administration of Fospropofol Disodium C_(max) Maximum value:Dose Mean (SD) Minimum Maximum SDs above the CV (mg) (ng/mL) (ng/mL)(ng/mL) mean (%)  200 69 (44) 35.08 191.02 2.74 64  400 201 (128) 33.47498.55 2.32 63  800 362 (376) 127.49 1352.75 2.64 99   1000 ^(a) 403(122) 266.72 681.00 2.28 30 1200 641 (292) 193.37 1188.45 1.87 46 1600748 (331) 228.54 1171.27 1.28 44 2000 806 (409) 199.53 1615.57 1.98 51Values are means (SD), or median (range) for T_(max). ^(a) n = 10subjects in each dose cohort, except the 1000-mg cohort for propofol (n= 9).

Table 16-3 illustrates that the highest observed C_(max) values withinthe 200, 400, 800, and 1000 mg cohorts were greater than 2 standarddeviations above the mean for that cohort. The highest observed C_(max)values in the 200, 400, 800, and 1000 mg cohorts were more than 2 timesthe mean C_(max) value for the respective cohort. In the 800-mg cohort,the highest observed C_(max) value was 1352.75 ng/mL, a valueapproximately 3.7-fold higher than mean value of C_(max) (362 ng/mL) forthe 800 mg cohort. Analyses to explore the role of subject-relatedfactors potentially predictive of unusually high C_(max) values, e.g.,weight, BMI, sex, age, serum alkaline phosphatase did not identify anypredictive factor.

TABLE 16-4 Propofol exposure by subject (800 mg Cohort). Subject CmaxTmax AUC1 AUC2 AUC4 Fe- No. ng/mL hr ng · h/mL ng · h/mL ng · h/mL male301 157.83 3 98.10 237.31 397.29 1 303 204.51 3 97.97 244.69 359.96 1304 279.41 1 153.18 259.05 337.29 0 305 255.22 1.5 124.03 334.03 614.191 307 399.94 1.5 193.54 372.18 523.43 1 308 1352.75 0.5 480.16 743.01922.96 1 309 227.29 1.5 111.55 227.07 321.62 0 310 264.22 1.5 171.46340.01 460.08 0 311 127.49 2 79.38 158.72 227.73 0 312 351.47 2 190.10411.20 572.00 1 Mean 362.01 1.75 169.95 332.73 473.66 SD 357.55 0.79116.21 163.24 198.58 CV (%) 98.8% 45.2% 68.4% 49.1% 41.9%

TABLE 16-5 Propofol exposure by subject (800 mg Cohort) omitting datafrom Subject 308, who demonstrated very high outlier exposure. SubjectCmax Tmax AUC1 AUC2 AUC4 Fe- No. ng/mL hr ng · h/mL ng · h/mL ng · h/mLmale 301 157.83 3 98.10 237.31 397.29 1 303 204.51 3 97.97 244.69 359.961 304 279.41 1 153.18 259.05 337.29 0 305 255.22 1.5 124.03 334.03614.19 1 307 399.94 1.5 193.54 372.18 523.43 1 308 1 309 227.29 1.5111.55 227.07 321.62 0 310 264.22 1.5 171.46 340.01 460.08 0 311 127.492 79.38 158.72 227.73 0 312 351.47 2 190.10 411.20 572.00 1 Mean 251.931.89 135.48 287.14 423.73 SD 86.55 0.70 42.75 81.23 127.77 CV (%) 34.4%36.9% 31.6% 28.3% 30.2%

TABLE 16-6 Propofol exposure by subject (800 mg Cohort) omitting datafrom Subject 308, females only. Subject Fe- No. Cmax Tmax Auc1 Auc2 Auc4male 301 157.83 3 98.10 237.31 397.29 1 303 204.51 3 97.97 244.69 359.961 304 0 305 255.22 2 124.03 334.03 614.19 1 307 399.94 2 193.54 372.18523.43 1 308 1 309 0 310 0 311 0 312 351.47 2 190.10 411.20 572.00 1Mean 273.79 2.20 140.75 319.88 493.37 SD 100.67 0.76 47.83 77.05 110.36CV (%) 36.8% 34.5% 34.0% 24.1% 22.4%

TABLE 16-7 Fospropofol Exposure by subject. Subject Cmax Tmax AUC1 AUC2AUC4 Fe- No. ng/mL hr ng · h/mL ng · h/mL ng · h/mL male 301 7942.730.25 2690.24 2988.84 3040.44 1 303 5546.32 0.33 2805.69 3782.78 4067.251 304 5265.38 0.25 2328.26 2497.80 2497.80 0 305 9361.51 0.33 3662.374416.94 4632.93 1 307 8555.93 0.50 4155.53 5002.09 5157.89 1 308 4964.970.33 2717.73 2909.41 2981.03 1 309 4768.77 0.42 2698.85 3555.61 3676.430 310 5211.25 0.25 2441.52 2661.24 2661.24 0 311 4763.18 0.25 2010.862308.48 2367.38 0 312 4031.53 0.50 2257.18 3141.45 3313.27 1 Mean6041.16 0.34 2776.82 3326.46 3439.57 SD 1854.40 0.10 656.02 865.72934.21 CV (%) 30.7% 29.2% 23.6% 26.0% 27.2%

TABLE 16-8 Fospropofol exposure by patient (females only). Subject Fe-No. Cmax Tmax Auc1 Auc2 Auc4 male 301 7942.73 0.25 2690.24 2988.843040.44 1 303 5546.32 0.333 2805.69 3782.78 4067.25 1 304 0 305 9361.510.333 3662.37 4416.94 4632.93 1 307 8555.93 0.5 4155.53 5002.09 5157.891 308 4964.97 0.333 2717.73 2909.41 2981.03 1 309 0 310 0 311 0 3124031.53 0.5 2257.18 3141.45 3313.27 1 Mean 6733.83 0.37 3048.12 3706.923865.47 SD 2169.22 0.10 710.67 855.43 901.99 CV (%) 32.2% 27.3% 23.3%23.1% 23.3%

The preliminary PK data from Study A16, Part 1, indicated that exposureto propofol (both C_(max) and AUC) after oral administration offospropofol disodium was approximately dose proportional over the doserange of 200 to 2000 mg. Within each dose cohort, the intersubjectvariability for propofol exposure was greater than for fospropofol. Mostof the dosing cohorts were characterized by the observation of 1 subjectwith unusually high propofol exposure. Analyses to explore the role ofsubject-related factors potentially predictive of unusually high C_(max)values, e.g., weight, BMI, sex, age, serum alkaline phosphatase, did notidentify any predictive factor.

Part 2: PK of a Single Dose of 1200 mg Fospropofol Disodium Following aHigh-Fat Meal

Part 2 of Study A16 was a double-blind, placebo-controlled, single-dosepilot study to investigate the PK, safety, and tolerability of 1200 mgof fospropofol disodium administered to healthy adult men and womenfollowing a high-fat meal.

Subjects were healthy adults (age 18-55 years inclusive, BMI 18-29.9kg/m²). A separate cohort of 15 subjects was randomly assigned toreceive a single oral dose of either fospropofol disodium (n=12) ormatching placebo (n=3) within 30 minutes (f1 minute) after the start ofa standardized high-fat meal.

Subjects were admitted to the clinical unit for an overnight fast (Day−1), administered study drug on Day 1 within 30 minutes of the start astandardized high-fat meal, and remained in the clinical unit until Day2.

Fospropofol disodium was formulated as powder in 6 HPMC capsules, eachcapsule containing 200 mg of fospropofol disodium (weight adjusted forwater content). Placebo was administered as 6 matching capsules.

Blood samples were collected for analysis of fospropofol and propofol atpredose, 5, 10, 15, 20, 25, 30, 37, and 45, minutes and 1, 2, 4, 6, and9 hours after dosing.

The following PK parameters were determined for fospropofol and propofolfrom plasma: area under the curve from time of dosing to last measuredtime point (AUC_(0-t)), area under the curve from time of dosingextrapolated to infinity (AUC_(0-inf)), residual area, maximum plasmaconcentration (C_(max)), time to maximum concentration (T_(max)),t_(1/2), apparent clearance (Cl/F), and apparent volume of distribution(Vd/F).

PK parameters from the fed cohort (Cohort 8, 1200 mg) are summarizedtogether with the parameters from the fasted cohort that received 1200mg (Cohort 5, Part 1) in Table 16-9. Mean concentrations are plottedover time for fospropofol and propofol by cohort in FIG. 2 .

Compared with subjects in Part 1 who received 1200 mg of fospropofoldisodium under fasting conditions, subjects who received 1200 mg offospropofol disodium following a high-fat meal showed a significantreduction in exposure (Table 16-9). Mean exposure to fospropofol underfed conditions (both C_(max) and AUC) was approximately 24% of theexposure under fasting conditions, with no appreciable effect on T_(max)(median, 0.333 h). For propofol, the mean AUC following a high-fat mealwas approximately 40% of the mean AUC observed under fasting conditions,and the mean C_(max) under fed conditions was approximately 19% of themean C_(max) observed under fasting conditions. Administration offospropofol disodium after a high-fat meal delayed the propofol T_(max)from a median value of 0.617 (range, 0.417-2.00) hours under fastingconditions to a median value of 2.00 (range, 0.500-4.00) hours.

TABLE 16-9 Study A16: PK Parameters for Fospropofol and Propofol afterOral Administration of fospropofol disodinm 1200 mg in the Fasted(Cohort 5) and Fed (Cohort 8) State Analyte/ AUC_(0-T) AUC_(0-∞) C_(max)T_(max) t_(1/2) CL/F Condition (ng · h/tnL) (ng · h/mL) (ng/mL) (h) (h)(L/h) Fospropofol Fasted (Cohort 5) 4399 (1425) 4502 (1410) 7110 (1613)0.33 (0.25-0.50) 0.34 (0.07) 288 (82) n = 10 Fed (Cohort 8) 993 (970)1076 (1012)^(a) 1792 (1661) 0.33 (0.08-0.62) 0.26 (0.15)a 4122(4829)^(a) n= 12 Propofol Fasted (Cohort 5) 1011 (275) 1010 (257) 641(292) 0.62 (0.42-2.0) 2.06 (0.94) 1260 (326) n = 10 Fed (Cohort 8) 478(174) 450 (450)^(b) 116 (42) 2.00 (0.50-4.0) 2.29 (0.67)^(b) 3111(1511)^(b) n= 12 Values are means (SD), or median (range) for T_(max),of data. ^(a)Values based on n = 10/12 subjects because of insufficientdata points to estimate elimination phase. ^(b)Values based on n = 7/12subjects because of insufficient data points to estimate eliminationphase.

Results of the pilot food-effect study indicate that administration offospropofol disodium 1200 mg within 30 minutes after the start of ahigh-fat meal is associated with a significant reduction in exposure toboth fospropofol and propofol.

Example A17, Study A17

Open-label study to describe the pharmacokinetics, and safety,tolerability, and relief of pain and associated migraine symptoms(nausea/vomiting, photophobia, phonophobia) following a single oral doseof fospropofol administered to adult women and men experiencing moderateto severe migraine headache.

-   -   Study Drug Fospropofol Disodium    -   Study Phase and Type Phase 1b—Open-label, single-dose        administration to adults with moderate to severe migraine        headache    -   Objectives Primary Objectives        -   To describe the pharmacokinetics (PK) of a single oral dose            of fospropofol administered to adult women and men            experiencing moderate to severe migraine headache.        -   To describe safety-tolerability of a single oral dose of            fospropofol administered to adult women and men experiencing            moderate to severe migraine headache.        -   Exploratory Objectives        -   To assess the clinical course (relief of pain and associated            migraine symptoms: nausea/vomiting, photophobia,            phonophobia) after a single oral dose of fospropofol            administered to adult women and men experiencing moderate to            severe migraine headache.        -   To explore the influence of covariates on PK and to            characterize pharmacokinetic-pharmacodynamic (PK-PD)            relationships between plasma propofol concentration and PD            assessments (measures of pain, associated migraine symptoms,            and sedation).    -   Study Design This is a Phase 1b, multicenter study with an        open-label, single-dose design in adult women and men with a        history of episodic migraine with or without aura, diagnosed        based on the International Classification of Headache Disorders,        edition 3 (ICHD-3). (Headache Classification Committee of the        International Headache Society (IHS). The International        Classification of Headache Disorders, 3rd edition. Cephalalgia        2018; 38:1-211) Migraine diagnosis will be confirmed in a        virtual (online) interview with a specialist in headache        medicine. The study is planned to complete approximately 85        subjects.        -   Enrolled subjects will be asked to come to the study site            for treatment when they experience a qualifying migraine            headache. Dosing must occur within 4 hours after onset of            the migraine symptoms. If treatment at the study site is not            feasible or practicable within 4 hours after onset of            migraine symptoms, subjects should use their usual            medication for that headache and attempt to visit the clinic            for treatment as soon as possible (within 4 hours) after            onset of their next migraine headache. Dosing must occur            within 60 days after enrollment (see Post-enrollment Period            below).        -   At clinic check-in for treatment, study personnel will            verify eligibility for dosing regarding the criteria for a            qualifying headache and adherence to post-enrollment study            restrictions (see Eligibility for Dosing below).        -   Treatment will consist of a single oral dose of fospropofol            disodium. Blood samples will be drawn for assessment of PK            parameters for fospropofol and propofol predose and during a            postdose period of 4 hours after dosing (see PK Sampling            below).        -   Safety assessments will be performed throughout. Headache            pain and associated migraine symptoms will be assessed at 1,            2, and 4 hours after dosing and at clinic discharge            (check-out).        -   Persistence or recurrence of migraine pain and other            symptoms will be assessed at Day 2 and Day 3 follow-up            telephone interviews.        -   Participants are considered to have completed the study if            they have been dosed with fospropofol disodium within 60            days after enrollment and if they have completed all            procedures listed in the Schedule of Events for Day 1, the            virtual (online) interview with the specialist in headache            medicine, and the follow-up telephone interviews on Days 2            and 3.    -   Justification for Dose Selection of the dose for this study is        based on the results of the prior Phase 1a study in healthy        volunteers (Study A16).    -   Safety Committee A Safety Review Committee will be established        to review periodic summaries of safety data from this study and        to provide consultation as outlined in the Safety Committee        Charter.    -   Subject Selection The study is planned to complete approximately        85 subjects. Because the prevalence of migraine headaches is        higher in women than in men, efforts will be made to enroll at        least 50% women.        -   Subjects must meet the general inclusion and exclusion            criteria listed below (Inclusion Criteria and Exclusion            Criteria) at screening to be enrolled in the study. To be            eligible for fospropofol disodium treatment after onset of a            migraine headache, enrolled subjects must meet criteria            specific to the presenting headache at clinic check-in (see            Qualifying Headache below) and adhere to study restrictions            specific to the period between enrollment and clinic            check-in (see Post-enrollment Restrictions below).    -   Inclusion Criteria Subjects must meet all of the following        criteria at screening to be enrolled in the study:        -   1. Written informed consent approved by the Institutional            Review Board (IRB) given before any study-related procedures            are performed        -   2. Male or female, ≥18 and ≤55 years of age at the time of            signed informed consent, with a body mass index (BMI) ≥18.0            and ≤29.9 kg/m² and body weight ≥50.0 kg for men and ≥45.0            kg for women.        -   3. History of episodic migraine (Katsarava Z. Buse D C,            Manack A N, et al (2012). Defining the differences between            episodic migraine and chronic migraine. Current pain and            headache reports, 16(1):86-92) consistent with a diagnosis            of migraine with or without aura according to the ICHD-3            criteria, plus the following:        -   a) Migraine attacks present for >1 year with age of onset            <50 years.        -   b) History of 2 to 8 migraine attacks with moderate or            severe pain per month (at least 8 hours in duration if            untreated or any duration if treated) in each of the 3            months prior to the screening visit.        -   4. Subjects who are treated with drugs intended for migraine            prophylaxis or drugs prescribed for a purpose other than            migraine prophylaxis but with a potential prophylactic            effect on migraine are eligible if they have been on a            stable regimen for at least 3 months and meet other            inclusion/exclusion criteria.        -   5. Female subjects must fulfill at least one of the            following:        -   a) Surgically sterile, defined as women who have had a tubal            ligation, hysterectomy, or bilateral oophorectomy at least 6            months prior to screening.        -   b) Post-menopausal, defined as absence of menses for at            least 12 months prior to screening.        -   c) Women who are sexually active and at risk for pregnancy            must agree to avoid pregnancy and use a medically acceptable            method of contraception from at least 30 days prior to            screening until 30 days after study drug administration.            -   Medically acceptable methods of contraception include                hormonal contraception, hormonal or non-hormonal                intrauterine device, double barrier method (simultaneous                use of male condom with intravaginally applied                spermicide and diaphragm or cervical cap), or male                partner vasectomy at least 6 months previously. Complete                abstinence alone can be used as a method of                contraception.        -   6. Male subjects who are not vasectomized for at least 6            months, and who are sexually active with a non-sterile            female partner (see definitions of surgically sterile and            post-menopausal above) must be willing to use one of the            following acceptable contraceptive methods throughout the            study and for 90 days after the study drug administration            (Complete abstinence alone can be used as a method of            contraception):        -   a) Simultaneous use of male condom and, for the female            partner, intrauterine contraceptive device with or without            hormone release (placed at least 4 weeks previously)        -   b) Simultaneous use of male condom and, for the female            partner, hormonal contraception        -   c) Simultaneous use of male condom and, for the female            partner, intravaginally applied spermicide with diaphragm or            cervical cap        -   7. Able to comprehend the nature of the study, capable of            giving written informed consent, and able to communicate            effectively with clinic staff (as assessed by the            investigator)        -   8. Available to volunteer for the entire study duration and            willing to adhere to all protocol requirements, including            the post-enrollment restrictions (see Post-enrollment            Restrictions below)        -   9. Agrees not to post any information related to the study            on any website or social media site (e.g., Facebook,            Twitter, LinkedIn, Google+, etc.) until the entire trial has            been completed        -   10. Willing to forgo rescue medicine for at least 2 hours            after initiation of treatment with study drug (see In-Clinic            Rescue Medicine)    -   Exclusion Criteria Subjects to whom any of the following        criteria apply at screening will be excluded:        -   1. History of hemiplegic migraine (at any time in the past).        -   2. History of headaches of any type occurring on ≥15            days/month during any of the 3 months prior to screening.        -   3. If subject has coexisting history of tension-type            headaches and migraine, inability to distinguish between            tension-type headaches and migraine.        -   4. In the investigator's judgment, overuse of medication for            migraine or other conditions, defined as use of any of the            following in any of the 3 months prior to screening:        -   a) Narcotics (opioids) ≥5 days/month (Opioids are allowed as            second-line treatment as long as they were used <5            days/month), or        -   b) Sedative-hypnotic drugs, (e.g., benzodiazepines,            barbiturates, sleeping aids, combination analgesic            medications containing butalbital) ≥8 days/month, or        -   c) Triptans (e.g., sumatriptan, naratriptan, almotriptan,            etc.) or ergotamine ≥8 days/month, or        -   d) Simple analgesics (e.g., aspirin, NSAIDs, acetaminophen,            caffeinated analgesic combinations) ≥12 days/month            (Occasional use of topical products without significant            systemic absorption is permitted.)        -   e) Anti-emetics, diphenhydramine ≥10 days/month.        -   f) Gepants: calcitonin gene-related peptide (CGRP) receptor            antagonists (e.g., ubrogepant, rimegepant) 10 days/month.        -   g) Ditans (lasmiditan) ≥10 days/month.        -   h) Herbal supplements and natural health products used for            acute treatment of migraine 210 days/month.        -   5. History of any of the following:        -   a) Clinically significant history of endocrine,            cardiovascular, pulmonary, hematologic, immunologic,            gastrointestinal, renal, hepatic, or metabolic disease; or            psychiatric conditions, major depression, dementia, or            significant neurological disorders other than migraine that            in the investigator's judgment would interfere with the            study, or        -   b) Active malignancy of any type or a history of malignancy            within the last 5 years (except basal cell carcinoma of the            skin that has been excised at least 12 weeks prior to study            start), or        -   c) Major surgery within 6 months prior to screening, unless            the investigator deems the subject eligible (minor surgery            performed 4 or more weeks prior to screening would not be a            reason for exclusion), or        -   d) Pain syndrome other than migraine that in the            investigator's judgment would interfere with the study, or        -   e) Diagnosis of sleep apnea, or        -   f) Any other medical condition that, in the opinion of the            investigator or the Sponsor, may be potentially associated            with an increased risk to the subject from study drug or to            participation in the study.        -   6. Positive serologic test for hepatitis B, hepatitis C, or            HIV at screening. (Reflex HCV RNA testing will be performed            for any positive hepatitis C screening test. If the results            of reflex testing are negative, the subject may be deemed            eligible for the study.)        -   7. Subjects who have any of the following at screening:        -   a) Clinically significant abnormality at physical            examination (in the judgment of the investigator), or        -   b) Clinically significant ECG abnormalities (in the judgment            of the investigator), or        -   c) Vital sign abnormalities (systolic blood pressure [BP]<90            mmFHg or >145 mmHg, diastolic blood pressure <55 mmHg or >95            mmHg, or heart rate [HR]<50 bpm or >110 bpm), or        -   d) Oxygen saturation by oximetry (SpO₂)<93%, or        -   e) Hemoglobin <135 g/L for men or <120 g/L for women        -   f) Clinically significant abnormal laboratory test results            (out of the study laboratory's acceptable range, unless            out-of-range values are deemed by the investigator to be not            clinically significant).        -   8. Subjects with a history of any of the following:        -   a) Significant alcohol abuse within 1 year prior to            screening or regular use of alcohol within 6 months prior to            screening (more than 14 units of alcohol per week [1            unit=150 mL of wine, 360 mL of beer, or 45 mL of 40%            alcohol]), or        -   b) Significant drug abuse or use of cocaine, phencyclidine            [PCP], crack, opioid derivatives including heroin, or            amphetamine derivatives, or similar drugs within 1 year            prior to screening, or significant use of marijuana or            tetrahydrocannabinol [THC]-containing products that in the            investigator's judgment is medically significant in that it            would impact the safety of the subject or the interpretation            of the study results.        -   c) Use of tobacco or nicotine products within 3 months prior            to screening.        -   9. Subjects who have any of the following at screening:        -   a) A positive alcohol breath test or        -   b) A positive urine drug screen (unless consistent with an            ongoing prescription drug as documented by the investigator)            (Note that detectable levels of marijuana (THC or            metabolites) in the urine drug screen are not exclusionary            if in the investigator's documented opinion the positive            test does not signal a clinical condition that would impact            the safety of the subject or interpretation of the study            results.) or        -   c) A positive urine cotinine test        -   10. Women who are pregnant (have a positive urine pregnancy            test at screening) or who are lactating        -   11. Subjects who have a history of severe allergic reactions            (e.g., anaphylactic reactions, angioedema),            hypersensitivity, or idiosyncratic reaction to fospropofol,            propofol, or related substances.        -   12. Subjects who have participated in an interventional            clinical research study involving:        -   a) Administration of an investigational or marketed drug or            device within 30 days prior to dosing with fospropofol            disodium, or        -   b) Administration of a biological product in the context of            a clinical research study within 90 days prior to dosing            with fospropofol disodium            -   (Concomitant participation in an investigational study                involving no drug or device administration is permitted,                provided obligations associated with the concomitant                participation are not expected to interfere with                procedures and obligations of the present study.)        -   13. Subjects who have intolerance to and/or difficulty with            blood sampling through venipuncture        -   14. Employees or immediate families (defined as spouse,            significant-other, parent, child, or sibling, whether            adopted or biologic) of an employee of Epalex Corporation,            its affiliates, or partners; investigator or study center            personnel directly affiliated with this study and/or their            immediate families.        -   15. Subjects who have a condition or are in a situation that            in the investigator's opinion may put the subject at            significant risk, may confound the study results, or may            interfere significantly with the subject's participation in            the study.        -   16. Score of >0 on the Sheehan Suicidality Tracking Scale            (S-STS) for a recall period of 30 days prior to screening.    -   Eligibility for Dosing: Qualifying Headache To qualify for        treatment with study drug, the presenting headache must meet the        following criteria:        -   1. Headache onset (assessed at phone call notifying clinic            staff of headache onset)        -   a) Subject was free of migraine symptoms for at least 48            hours before the start of symptoms of the migraine headache            to be treated (and did not take medications for the acute            treatment of migraine during this period).        -   b) Time between onset of the symptoms of the migraine            headache to be treated and estimated time of treatment must            be less than 4 hours.        -   2. At clinic check-in        -   a) Time between onset of the symptoms of the migraine            headache to be treated and actual time treatment must be            less than 4 hours.        -   b) Moderate or severe pain intensity (2 or 3 on a 4-point            Likert scale where 0=none, 1=mild, 2=moderate, 3=severe).        -   c) Has at least 1 of the following characteristics:            unilateral location, throbbing (pulsating), or aggravated by            routine physical activity.        -   d) Associated with at least 1 of the following symptoms:            nausea/vomiting, photophobia, or phonophobia.        -   3. Within 10 minutes before dosing        -   a) Moderate or severe pain intensity (2 or 3 on a 4-point            Likert scale where 0=none, 1=mild, 2=moderate, 3=severe).        -   b) Presence of at least 1 symptom (nausea/vomiting,            photophobia, or phonophobia).    -   Eligibility for Dosing: Post-enrollment Study Restrictions The        following restrictions specific to the period after enrollment        must be met for treatment of a migraine with fospropofol        disodium to occur.        -   Medications Permitted with Restrictions        -   If the subject experiences a migraine headache where study            treatment is not feasible or practicable, the following            medications for acute migraine treatment are allowed after            enrollment, as agreed with the investigator at screening,            provided the following restrictions to prevent overuse are            met and provided the subject has not taken them within 48            hours prior to clinic check-in (see Point 3 under Restricted            and prohibited substances or products below):        -   1. Narcotics (opioids) as second-line treatment only: No            more than 4 days/month or in the 30 days prior to dosing.        -   2. Sedative-hypnotic drugs, (e.g., benzodiazepines,            barbiturates, sleeping aids, combination drugs containing            butalbital): No more than 7 days/month or in the 30 days            prior to dosing.        -   3. Triptans (e.g., sumatriptan, naratriptan, almotriptan,            etc.) or ergotamine: No more than 7 days/month or in the 30            days prior to dosing.        -   4. Analgesics, alone or in a combination product (e.g.,            aspirin, NSAIDs, acetaminophen, caffeinated analgesic            combinations): No more than 11 days/month or in the 30 days            prior to dosing.        -   5. Anti-emetics, diphenhydramine. No more than 9 days/month            or in the 30 days prior to dosing.        -   6. Gepants: CGRP receptor antagonists (e.g., ubrogepant,            rimegepant). No more than 9 days/month or in the 30 days            prior to dosing.        -   7. Ditans: lasmiditan. No more than 9 days/month or in the            30 days prior to dosing.        -   8. Herbal supplements and natural health products used for            acute treatment of migraine. No more than 9 days/month or in            the 30 days prior to dosing.        -   Restricted and prohibited substances or products        -   1. Alcohol-based products are to be restricted as follows:        -   a) No more than 14 units of alcohol per week [1 unit=150 mL            of wine, 360 mL of beer, or 45 mL of 40% alcohol])        -   b) Fospropofol disodium dosing is not to be performed if            subject consumed alcohol within 24 hours prior to clinic            check-in (Alcohol breath test must be negative at check-in)        -   2. The following products are not permitted at any time            during study participation (from enrollment until after            study completion [after the Day 3 telephone call]):        -   a) Cocaine, phencyclidine [PCP], crack, opioid derivatives            including heroin, amphetamine derivatives, or similar drugs,            and marijuana or tetrahydrocannabinol [THC]-containing            products. Urine drug screen must be negative at check-in.            (Foods containing poppy seeds should be avoided during study            participation because they may interfere with results of the            urine drug screen.) Note that detectable levels of marijuana            (THC or metabolites) in the urine drug screen at check-in            are not exclusionary for dosing if in the investigator's            documented opinion the positive test does not signal a            clinical condition that would impact the safety of the            subject or interpretation of the study results and documents            that the subject affirms that they have not used any            marijuana or THC-containing product within the 48 hours            prior to the onset of migraine symptoms        -   b) Any tobacco or nicotine products (Urine cotinine test            must be negative at check-in.)        -   3. Fospropofol disodium dosing is not to be performed if the            subject has taken any of these medications within 48 hours            prior to clinic check-in:        -   a) Narcotics (opioids), sedative-hypnotic drugs, (e.g.,            benzodiazepines, barbiturates, sleeping aids, combination            drugs containing butalbital).        -   b) Triptans (e.g., sumatriptan, naratriptan, almotriptan,            etc.) or ergotamine.        -   c) Analgesics, alone or in a combination product (e.g.,            aspirin, NSAIDs, or acetaminophen).        -   d) Anti-emetics, diphenhydramine.        -   e) Gepants: CGRP receptor antagonists (e.g., ubrogepant,            rimegepant).        -   f) Ditans: lasmiditan.        -   g) Herbal supplements and natural health products used to            treat migraine.        -   h) Marijuana or THC-containing products            -   Other Restrictions            -   Dosing is not to be performed if any of the following                conditions apply.        -   1. Events within 30 days prior to clinic check-in:        -   a) Significant illness or any surgical procedure        -   b) Subject donated plasma or blood        -   2. Any vaccination (e.g., COVID-19 vaccination, influenza)            within 10 days prior to clinic check-in.        -   3. Tension-type headaches occurring on ≥15 days in any month            since enrollment.        -   4. Clinically significant abnormalities at physical            examination or in ECG, vital signs, SpO₂, hemoglobin, or            other laboratory results (as defined under Exclusion            Criteria for screening, Point 7). At clinic check-in,            elevations in BP and/or pulse attributable to headache pain            or other migraine symptoms may be accepted according to the            investigator's judgment.        -   5. Positive urine pregnancy test at clinic check-in.        -   6. Abnormal diet patterns (for any reason) during the 4            weeks preceding clinic check-in, including fasting, high            protein diets etc.        -   7. Subject has a response on the S-STS greater than zero to            any question other than Question 2 and a response greater            than 1 on Question 2. (Subjects with a response of 1 to            Question 2 will be discontinued at the discretion of the            investigator.)        -   8. Conditions or situations arising since clinic enrollment            that in the investigator's opinion, may put the subject at            significant risk or may confound the study results.            -   Permitted Throughout the Study        -   1. Standard migraine prophylactic medications and other            medications with a prophylactic effect on migraines are            permitted as prescribed, provided that no changes in dose            are made during the study. Prophylactic medications may not            be started during the study.        -   2. Hormonal contraception and routine use of            over-the-counter (OTC) multivitamins for general health are            permitted throughout the study.        -   3. Other prescription medications and OTC medicines are            permitted if medically necessary as agreed with the            investigator on a case-by-case basis at screening.        -   4. Herbal supplements and health products are permitted if            agreed with the investigator on a case-by-case basis at            screening.    -   In-Clinic Rescue Medicine Rescue medicine may be administered in        the clinic at the discretion of the investigator at any time        after fospropofol disodium dosing if additional medication for        acute treatment of migraine pain is necessary. However,        investigators and subjects will be encouraged to avoid        administration of rescue medication earlier than 2 hours after        fospropofol disodium dosing.        -   In general, the investigator and subject will agree at            screening on the appropriate rescue therapy for the subject.            Subjects must supply their own rescue medication at clinic            check-in.        -   Selection of in-clinic rescue medication for each subject            may be guided by treatment that was effective for the            subject in the past. First-line rescue therapy may include            an analgesic and/or acute migraine medication and will not            include narcotics. If necessary, a second-line rescue            therapy may be agreed upon at the investigator's discretion.        -   The following products may be agreed upon between subject            and investigator at screening to be used as rescue            medication if required in the clinic after dosing with            fospropofol disodium:        -   1. Analgesics, alone or in a combination product, including            acetaminophen, aspirin, or NSAIDs.        -   2. Triptans (e.g., sumatriptan, naratriptan, almotriptan).        -   3. Gepants (CGRP antagonists, e.g., ubrogepant, rimegepant).        -   4. Ditans (lasmiditan).        -   Because of the potential for additive cardiorespiratory            effects when narcotic analgesics and sedative-hypnotic            agents (e.g., opiates, benzodiazepines, barbiturates,            sleeping aids, combination drugs containing butalbital) are            administered concomitantly with fospropofol disodium, these            medications are not recommended as rescue therapy after            fospropofol disodium dosing. Prescription anti-emetics,            including metoclopramide, prochlorperazine, chlorpromazine,            as well as OTC drugs sometimes helpful for nausea, such as            dimenhydrinate, meclizine, and diphenhydramine, are            associated with sedation and should be avoided as rescue            treatment until at least 4 hours after treatment with            fospropofol disodium.    -   Study Drug and Dosage Form Fospropofol disodium is formulated        for oral administration in an appropriate number of        powder-filled hydroxypropyl methylcellulose (HPMC) capsules.        Each HPMC capsule contains 200 mg of fospropofol disodium        (uncorrected for sodium content) and no inactive ingredients. It        is possible that capsules containing smaller amounts of        fospropofol disodium (i.e., 100 mg) may also be used.    -   Dose Level/Dose Adjustment Initially, all subjects will receive        1 oral dose of 800 mg of fospropofol disodium. After completion        of 10 subjects, and depending on tolerability and PK results,        the dose may be modified for the remaining subjects, for example        by reducing the dose for all subjects or for a subset of        subjects with low body weight or by increasing the dose for all        subjects or for a subset of subjects with high body weight. Any        upward dose adjustment (for all or for a subset of subjects)        will require unanimous approval by the Safety Committee. A        divided dose may also be considered, for example in which the        dose would be divided into 2 administrations separated in time        during the same study visit. It is also possible that the        Sponsor at its initiative, or if recommended by the Safety        Committee, may reduce the dose at any time during the study.    -   Administration of Study Drug Dosing must occur within 4 hours        after onset of migraine symptoms.        -   The study drug will be administered with water at ambient            temperature in the amount of approximately 240 mL [8 oz].            Except for water administered with the study drug, fluids            will not be permitted from dosing until 1 hour after dosing            (see Study Restrictions). Fluids will be permitted ad lib            thereafter.        -   As a safety precaution, subjects will be required to remain            seated or semi-reclined for 15 minutes before and for 4            hours after administration of study drug. During the 4 hours            after dosing, subjects may ambulate to the restroom at the            discretion of the investigator but must be accompanied by            study staff while walking to and from the restroom.        -   Subjects will be permitted to sleep ad lib (in a            semi-reclined position) after administration of study drug            but are to be awakened for the assessments of headache pain            and associated migraine symptoms at 1, 2, and 4 hours after            dosing.    -   Screening Procedures Screening procedures will comprise written        informed consent and review of inclusion/exclusion criteria,        including demographic data; body measurements (height, weight);        medical and migraine history; medication history (including drug        allergies); 12-lead ECG; pulse oximetry: vital signs (BP, HR,        RR, temperature), safety laboratory assessments (hematology,        blood chemistry, HIV, hepatitis B and C tests, urinalysis, urine        drug screen, alcohol breath test, urine cotinine test, urine        pregnancy test for women); complete physical examination, and        the Sheehan Suicidality Tracking Scale.        -   Migraine history will be obtained by subject interview and            will include age of onset and time since first attack;            estimated frequency of migraine episodes during the prior 3            months, including frequency of episodes classified as            moderate or severe; history of migraine-associated symptoms            (nausea/vomiting, photophobia, phonophobia, or other            symptoms); most bothersome symptom (nausea/vomiting,            photophobia, or phonophobia); characteristic features of            episodes (unilateral vs bilateral location, pulsating            quality, pain intensity, aggravation by or causing avoidance            of routine physical activity); presence and features of            aura, if any; and history of headache types other than            migraine and subject's ability to distinguish between            migraine and tension-type headaches.        -   A virtual (online) interview will be conducted with the            subject by a specialist in headache medicine to confirm the            migraine diagnosis according to ICHD-3 criteria. See            Headache Classification Committee of the International            Headache Society (IHS). The International Classification of            Headache Disorders, 3rd edition. Cephalalgia 2018; 38:1-211.        -   Medication history will be obtained by interview and will            include history of migraine-related medications during the 3            months prior to screening. Migraine-related medications            include medications (if any) used for first- and/or            second-line treatment of acute migraine and medications used            for migraine prophylaxis or that have prophylactic effect on            migraine. History of other medications will be recorded for            the 30 days prior to screening.        -   Medications expected to be used during the course of study            will be reviewed, recorded, and approved at screening by the            investigator (consultation with Sponsor will be available as            needed). Such medications include migraine medicine to be            used if treatment at the study site is not feasible within 4            hours after symptom onset (see Post-enrollment Period            below).        -   The investigator and subject are to agree at screening on an            appropriate rescue medication to be used if needed in clinic            after fospropofol disodium dosing (see Rescue Medication).        -   Subjects who give written informed consent and meet            inclusion/exclusion criteria will be enrolled in the study.            Enrolled subjects will receive instructions regarding            identification of a qualifying headache as well as            restrictions and procedures for the post-enrollment period.    -   Post-enrollment Period Enrolled subjects will be asked to come        to the study site for treatment with study drug as soon as        possible when they experience migraine symptoms, as dosing must        occur within 4 hours after symptom onset. If treatment at the        study site is not feasible or practicable within 4 hours after        the onset of migraine symptoms, subjects should use their usual        headache medication as agreed at screening and within the        parameters noted in the post-enrollment restrictions. This        situation may arise, for example, if the onset of symptoms        occurs outside of study site hours, or if family or work        circumstances make it impracticable for the subject to reach the        site for treatment within the 4-hour time frame. In such cases,        the subject should attempt to visit the clinic for treatment as        soon as possible (within 4 hours) after onset of their next        migraine headache.        -   Clinic admission for treatment of a qualifying headache is            to occur within 60 days after enrollment. Clinic staff are            to remain in contact with subjects as needed to address any            barriers that may prevent subjects from presenting for            treatment.        -   If an enrolled subject is not treated with fospropofol            disodium for a qualifying headache within 60 days after            enrollment, this situation is to be classified as “failure            to dose.” If possible, reasons for failure to dose within 60            days should be ascertained and recorded using the following            checklist of potential issues: lack of moderate to severe            headaches, work circumstances, family circumstances, lack of            adherence to post-enrollment restrictions, or other reasons.    -   Headache Onset Because dosing must be performed within 4 hours        after the onset of migraine symptoms, subjects will be        instructed to notify staff by calling the study site as soon as        possible when migraine symptoms start.        -   A comprehensive review of eligibility for dosing will be            performed only at clinic check-in. However, preliminary            eligibility for fospropofol disodium dosing should be            determined during the call to prevent an unnecessary trip to            the clinic. Therefore, subjects will be asked about the            start time of the migraine symptoms, whether they had            migraine symptoms during the 2 days before onset of this            migraine, whether they took medications or products that are            prohibited during the 48 hours before treatment, and whether            they had any recent medical events that might affect study            participation.        -   Subjects who do not meet the preliminary eligibility            criteria for dosing for the current headache are to be            instructed to take their usual headache medicine and to call            again as soon as possible after onset of their next migraine            headache.    -   Clinic Check-in The study staff is to perform the following        procedures at clinic check-in:        -   1. Take custody of agreed rescue medication.        -   2. Assess the presenting headache and associated symptoms        -   3. Perform safety assessments:        -   a) 12-lead ECG.        -   b) Pulse oximetry and vital signs.        -   c) Safety laboratory assessments, including urine drug,            cotinine, and pregnancy tests and alcohol breath test.        -   d) Abbreviated physical examination.        -   c) Sheehan Suicidality Tracking Scale (recall period since            screening)        -   4. Record subject's recollection of medications taken since            screening on concomitant medication log.        -   5. Record time and nature of last meal or food intake,            including beverages.        -   6. Review adherence to post-enrollment study restrictions.        -   7. Assess qualifying headache and associated symptoms within            10 minutes prior to dosing.    -   Confinement in Clinic Subjects will be confined to the study        site for approximately 5 hours after dosing of the study drug.        The duration of confinement may be extended for safety reasons        at the discretion of the investigator.    -   Clinic Check-out and Early Termination The following procedures        will be carried out at clinic check-out or for early termination        (when applicable): safety laboratory assessments (hematology,        blood chemistry, urinalysis, serum pregnancy test), vital signs        (BP, HR, RR, temperature), pulse oximetry, 12-lead ECG, headache        assessment, abbreviated physical examination, adverse events        (AEs).        -   Transportation from the clinic to the subject's home will be            arranged, and subjects will be instructed not to drive or            operate heavy machinery for 24 hours after dosing. Subjects            will be instructed that, if they have a persistent headache            or a new headache after discharge, they are permitted to            take their usual medication, as long as it is in accordance            with post-enrollment study restrictions, and that they will            be asked during the follow-up telephone interviews about            persistence or recurrence of headache pain and symptoms and            whether they took medication and when.        -   Arrangements for the follow-up telephone interviews will be            made.    -   Follow-up Telephone Interviews Follow-up telephone interviews        will be scheduled on Day 2 (between 24 and 32 hours after        dosing) and on Day 3 (between 48 and 56 hours after dosing) for        subjects to report and grade any ongoing migraine headache pain,        ongoing migraine-associated symptoms (present/absent),        recurrence or worsening of pain or migraine-associated symptoms,        medication taken, and occurrence of any AEs since clinic        discharge.    -   PK Sampling A total of 7 blood samples of 6 mL each will be        collected for analysis of fospropofol and propofol PK. The PK        samples will be collected at the following time points: predose        (within 120 minutes before dosing) and postdose at 10, 20, and        40 minutes and 1, 2, and 4 hours after dosing.        -   In case of a serious adverse event (SAE) or early            withdrawal, a PK blood draw should be performed if possible,            at or near the time the subject reports the SAE or at the            time of withdrawal from the study.    -   Safety Procedures and Assessments Medical Surveillance and AE        Monitoring Safety data will be evaluated on an ongoing basis by        the Safety Review Committee to ensure it is safe to continue        study enrollment and treatment.        -   The investigator is to be on site from approximately 30            minutes prior to each dosing until clinic discharge and            available on call until the second follow-up telephone            interview has been completed.        -   The study site is to be staffed to assess and manage            potential risks that may occur with sedative-hypnotic            agents. Subjects are to be continuously monitored for oxygen            desaturation using a pulse oximeter with an alarm, and            supplemental oxygen should be available. In addition,            although these conditions are unlikely to occur at the            selected dose of fospropofol disodium, subjects should be            monitored for early signs of hypotension, apnea, or airway            obstruction from approximately 30 minutes prior to dosing of            study drug until clinic discharge. This role may be            fulfilled by the investigator or designee trained in airway            management.        -   Safety parameters, including laboratory results and ECG,            will be evaluated by the investigator in the context of            clinical trial safety. Any abnormal measurement is to be            repeated if judged necessary by the investigator. Further            action to ensure subject safety may be taken at the            investigator's discretion. A board-certified cardiology            specialist will be available for consultation if an ECG            concern should arise in the course of the study.        -   12-Lead ECG        -   A 12-lead ECG will be performed at screening, clinic            check-in and clinic check-out.        -   Sleep Status        -   Subjects will be permitted to sleep ad lib (in a            semi-reclined position) after administration of study drug            but are to be awakened for the assessments of headache pain            and associated migraine symptoms at 1, 2, and 4 hours after            dosing.        -   The subject's sleep status will be recorded after dosing at            15-minute intervals through hour 4 (assessed as “appears to            be sleeping” or “appears to be awake”).        -   Pulse Oximetry        -   Pulse oximetry will be recorded at screening and            continuously monitored on Day 1 from at least 15 minutes            prior to dosing until discharge from the clinic. The pulse            oximeter is to have an alarm set to give both audible and            visual notifications when SpO₂ drops to 90% or below. If the            alarm signals, the subject should be aroused. Nasal oxygen            should be considered if SpO₂ remains at 90% or lower after            stimulation.        -   SpO₂ values will be recorded from the continuous monitor at            approximately the same time points as the sleep status            assessments (15-minute intervals).        -   Vital Signs        -   BP, HR, and RR will be recorded at screening, on Day 1            within 60 minutes before dosing, postdose at 30-minute            intervals until 4 hours after dosing, and at clinic            check-out. Temperature will be recorded at screening, on Day            1 within 60 minutes before dosing, and at clinic check-out.            If vital sign measurement times coincide with blood            collection for laboratory tests, vital signs are to be taken            within 5 minutes before the blood draw.        -   BP, HR, RR, temperature, and pulse oximetry will be recorded            with the subject in a seated or semi-reclined position. At            clinic check-in, elevations in BP or HR attributable to            headache pain or other migraine symptoms may be accepted            according to the investigator's judgment.        -   MOAA/S Score        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) score            at 4 hours after dosing. If the MOAA/S score is below 5 at 4            hours after dosing, and/or there is reason for concern, the            duration of confinement may be extended, and safety            monitoring may continue at the discretion of the            investigator. Cohen LB. Clinical trial: a dose-response            study of fospropofol disodium for moderate sedation during            colonoscopy. Aliment Pharmacol Ther 2008; 27:597-608. Chemik            D A, Gillings D, Lane H, et al. Validity and reliability of            the Observer's Assessment of Alertness/Sedation Scale: study            with intravenous midazolam. J Clin Psychopharmacol 1990;            10:244-251.        -   Safety Laboratory Assessments        -   Hematology, serum chemistry, and urinalysis will be assessed            at screening, at clinic check-in, and at clinic check-out.        -   Serologic tests for hepatitis B, hepatitis C, and HIV will            be performed at screening.        -   A urine drug screen, urine cotinine test, and alcohol breath            test will be performed at screening and clinic check-in.        -   For women, a urine pregnancy test will be performed at            screening and at clinic check-in. A serum pregnancy test            will be performed at clinic check-out for confirmation.        -   Physical Examination        -   A complete physical examination will be performed at            screening and abbreviated physical examinations will be            performed at clinic check-in and check-out.        -   Sheehan Suicidality Tracking Scale        -   The Sheehan Suicidality Tracking Scale will be administered            at the screening visit, at clinic check-in, and at the Day 3            telephone interview.    -   Total Blood Volume Drawn Total blood volume drawn per subject        will not exceed a maximum of 200 mL, including screening, PK,        and safety assessments.    -   Measures of Clinical Course (Exploratory) Headache pain and        associated migraine symptoms (nausea/vomiting, photophobia, and        phonophobia) will be recorded as migraine-related events.        Headache pain will be rated on a 4-point Likert scale (0=none,        1=mild, 2=moderate, 3=severe). Associated migraine symptoms        (nausea/vomiting, photophobia, and phonophobia) will be        classified as either present or absent.        -   Subjects will be asked to respond to questions regarding            headache pain and associated symptoms at clinic check-in,            within 10 minutes before dosing (baseline), at 1, 2, and 4            hours after dosing, at clinic check-out, and by telephone            interview on Day 2 and Day 3.    -   Adverse Events Subjects will be instructed to inform clinical        personnel of any potential AEs, i.e., untoward medical symptoms        and/or events that may arise from arrival at the clinic for        check-in until the final follow-up telephone interview.        -   Treatment-emergent adverse events (TEAEs) are defined as the            reported AEs that first occurred or worsened after            administration of the study drug. The incidence,            seriousness, severity, duration, and relation to study drug            of all TEAEs will be recorded.        -   Some degree of sedation is an expected and potentially            therapeutic effect of the study drug. Although sedation,            including events described as feeling “drowsy,” “sleepy,”            “relaxed,” etc., will be expected, such terms if expressed            by the subject will be recorded as AEs, and severity will be            rated by the site investigator as mild, moderate, or severe.            Because subjects will be encouraged to sleep after dosing if            desired, sleep itself will not be considered an AE.        -   Worsening or recurrence of migraine pain or related migraine            symptoms (nausea/vomiting, photophobia, phonophobia) during            the clinic visit or after discharge through the Day 3            follow-up interview will be recorded as migraine-related            events and will not be recorded as AEs.    -   Analytical Method Fospropofol and propofol concentrations will        be analyzed in plasma samples using a validated method.    -   Statistical Considerations Safety and Tolerability Safety and        tolerability data will be reported using descriptive statistics.        Summary statistics for TEAEs will be reported. Changes from        baseline values in vital signs, ECG, and clinical laboratory        parameters will be reported.        -   PK        -   Interim bioanalysis and PK analyses for fospropofol and            propofol are to be performed after approximately 10 subjects            have been completed, again after approximately 30 subjects            are completed, and may be performed at other intervals as            well.        -   Summary statistics will be used to describe the PK profile            of both fospropofol and propofol. Summary statistics will            include at minimum arithmetic and geometric means for            AUC_(0-t), AUC_(0-inf), and C_(max). T_(max) will be            characterized by median and range.        -   Exploratory Analyses        -   Clinical Course        -   Summary statistics of the subject's assessment of headache            pain (on the Likert scale) at 1, 2, and 4 hours postdose, at            clinic discharge, and at follow-up on Days 1 and 2 will be            reported.        -   Summary statistics of headache recurrence or worsening will            also be reported.        -   Summary statistics of the subject's assessment of the most            bothersome symptom (presence or absent) at 1, 2, and 4 hours            posidose, and at clinic discharge will be reported. Summary            statistics of recurrence or worsening of the most bothersome            symptom will also be reported.        -   Summary statistics of the subject's assessment of            migraine-associated symptoms other than the most bothersome            symptom as applicable (presence or absent) at 1, 2, and 4            hours postdose, and at clinic discharge will be reported.            Summary statistics of recurrence or worsening            migraine-associated symptoms will also be reported.        -   Summary statistics will be reported, including but not            limited to        -   (1) proportion of subjects reporting no headache pain at 2            hours;        -   (2) proportion of subjects reporting the absence of most            bothersome symptom at 2 hours; and (3) proportion of            subjects reporting improvement in pain (change from            severe/moderate to mild/absent) at 2 hours. All analyses            will be exploratory.        -   Influence of Covariates; PK-PD Relationships        -   Exploratory analyses will be performed in an effort to            characterize the influence of covariates on PK (e.g.,            relationship between plasma propofol concentrations and            gender, age, weight, and BMI) and to characterize PK-PD            relationships (e.g., relationship between plasma propofol            concentrations and AEs).        -   Exploratory analyses in an effort to characterize the            relationship between plasma propofol concentration (e.g.,            C_(max) and or partial AUC) and the clinical course of            migraine symptoms will also be performed. Details are to be            described in the SAP. Additional statistical analysis may be            performed. All analyses will be descriptive or exploratory            and not intended to test any specific hypothesis.

Study Assessments

A total of 7 blood samples of 6 mL each will be collected for analysisof fospropofol and propofol PK. The PK samples will be collected at thefollowing time points: predose (within 120 minutes before dosing) andpostdose at 10, 20, and 40 minutes and 1, 2, and 4 hours after dosing.

The time tolerance window for blood samples collected during theconfinement period will be ±1 minute for all samples. Sample collectionsdone outside the predefined time windows will not be considered asprotocol deviations since actual postdose sampling times will be usedfor PK and statistical analyses.

When appropriate, an indwelling i.v. catheter will be used for bloodcollection to avoid multiple skin punctures. Otherwise, blood sampleswill be collected by direct venipuncture.

In case of an SAE or early withdrawal, a PK blood draw should beperformed if possible, at or near the time the subject reports the SAEor at the time of withdrawal from the study.

Blood samples for safety laboratory assessments will be drawn atscreening, clinic check-in, and clinic discharge.

The total blood volume drawn per subject will not exceed a maximum of200 mL, including screening.

Safety Procedures and Assessments

Medical Surveillance and AE Monitoring

A 12-lead ECG will be performed at screening, at clinic check-in (within120 minutes before dosing) and at clinic check-out. Corrected QTinterval (QTc) will be recorded.

Subjects will be permitted to sleep ad lib (in a semi-reclined position)after administration of study drug but are to be awakened for theassessments of headache pain and associated migraine symptoms at 1, 2,and 4 hours after dosing.

The subject's sleep status will be recorded after dosing at 15-minuteintervals through hour 4 (assessed as “appears to be sleeping” or“appears to be awake”).

Pulse oximetry will be recorded at screening and continuously monitoredon Day 1 from at least 15 minutes prior to dosing until discharge fromthe clinic. The pulse oximeter is to have an alarm set to give bothaudible and visual notifications when SpO₂ drops to 90% or below. If thealarm signals, the subject should be aroused. Nasal oxygen should beconsidered if SpO₂ remains at 90% or lower after stimulation.

SpO₂ values will be recorded from the continuous monitor within 15minutes before dosing, postdose at approximately the same time points asthe sleep status assessments (15-minute intervals), and at cliniccheck-out, with the subject seated or semi-reclined.

Systolic and diastolic BP (mmHg), HR, and RR will be recorded atscreening, on Day 1 within 60 minutes before dosing, at 30-minuteintervals until 4 hours after dosing, and at clinic check-out ( ). Forconsistency with time points where they should be performed before PKblood draws, these assessments should take place within 10 minutesbefore each designated time point. Temperature (as degrees Fahrenheit)will be recorded at screening, on Day 1 within 60 minutes before dosing,and at clinic check-out.

BP, HR, and RR are to be assessed with the subject having been in aseated or semi-reclined position for at least 5 minutes. At cliniccheck-in, elevations of BP or HR attributable to headache pain or othermigraine symptoms may be accepted according to the investigator'sjudgment.

Level of sedation will be assessed using the MOAA/S score at 4 hoursafter dosing (within 10 minutes before the 4-hour PK blood draw). CohenLB. Clinical trial: a dose-response study of fospropofol disodium formoderate sedation during colonoscopy. Aliment Pharmacol Ther2008:27:597-608. Chemik D A, Gillings D, Laine H, et al. Validity andreliability of the Observer's Assessment of Alertness/Sedation Scale:study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244-251.

If the MOAA/S score is below 5 at 4 hours after dosing and/or there isreason for concern, the duration of confinement may be extended, andsafety monitoring may continue at the discretion of the investigator.

Safety Laboratory Assessments

Hematology

Hematology samples will be drawn at screening, clinic check-in, andclinic check-out. Hematology will include complete blood count withdifferential, hemoglobin, and hematocrit.

Serum Chemistry

Serum chemistry samples will be drawn at screening, clinic check-in, andclinic check-out. Serum chemistry assessments will include albumin,alanine aminotransferase, alkaline phosphatase, aspartateaminotransferase, calcium, chloride, carbon dioxide/bicarbonate,creatinine, glucose, phosphate, potassium, sodium, total bilirubin,total protein, and blood urea nitrogen (BUN).

Serology

Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIV antigen andantibody detection will be performed at screening. (Reflex HCV RNAtesting will be performed for any positive hepatitis C screening test.If the results of reflex testing are negative, the subject may be deemedeligible for the study.)

Urinalysis

Urine for urinalysis will be collected at screening, clinic check-in,and clinic check-out. Urinalysis will include macroscopic examination,pH, specific gravity, protein, glucose, ketones, bilirubin, occultblood, nitrite, urobilinogen, and leukocytes. Unless otherwisespecified, microscopic examination will be performed on abnormalfindings according to standard procedure.

Drug, Cotinine, and Alcohol

A urine drug screen (amphetamines, methamphetamines, barbiturates,benzodiazepines, THC, cocaine, opiates, PCP,3,4-methylenedioxy-methamphetamine (MDMA), methadone), a urine cotininetest, and an alcohol breath test will be performed at screening and atclinic check-in.

Pregnancy Tests

For women, a urine pregnancy test will be performed at screening and atclinic check-in. A serum pregnancy test will be performed at cliniccheck-out for confirmation.

Physical Examination

A complete physical examination will be performed at screening, andabbreviated physical examinations will be performed at clinic check-inand check-out.

The complete physical examination at the screening visit will assess anyphysical abnormalities and will include at a minimum, assessments of thefollowing body systems: general appearance, overall status of the head,ears, eyes, nose, throat (HEENT), neck, abdomen, lymph nodes, skin,cardiovascular/heart, pulmonary, musculoskeletal, and neurological(level of alertness [more detailed mental status not required unlessindicated], speech, cranial nerves, motor strength and tone, cerebellar,sensory, deep tendon reflexes, and gait). Investigators should payspecial attention to clinical signs related to previous seriousillnesses.

Height and weight will also be measured and recorded at the screeningvisit.

The abbreviated physical examination at check-in and check-out willassess general appearance, HEENT, cardiovascular, pulmonary, andneurological status. The neurological examination is to consist of levelof alertness and speech. Abbreviated physical examinations may belimited to recording change/no change from prior examinations, plusfocused examination by system as directed by any AEs reported by thesubject (where applicable) or any spontaneous symptom/complaint reportedby the subject at the time of the examination.

Sheehan Suicidality Tracking Scale

The Sheehan Suicidality Tracking Scale (S-STS) is a prospectivesuicidality rating scale to be completed by the investigator or his/herdesignate. The scale includes 16 questions that allow a longitudinalevaluation of treatment-emergent suicidal ideation andtreatment-emergent suicidal behaviors. Sheehan D V, Alphs L D, Mao L, etal. Comparative Validation of the S-STS, the ISST-Plus, and the C-SSRSfor Assessing the Suicidal Thinking and Behavior FDA 2012 SuicidalityCategories. Innov Clin Neurosci 2014; 11:32-46. Sheehan D V, Giddens JM, Sheehan I S. Status Update on the Sheehan-Suicidality Tracking Scale(S-STS) 2014. Innov Clin Neurosci 2014; 11:93-140.

The S-STS will be completed on a paper form at the site and will beadministered at the screening visit, at clinic check-in, and at the Day3 follow-up telephone interview. The recall period at the screeningadministration will encompass the time period beginning 30 days prior tothe screening visit; the recall period at clinic check-in will be thetime period since the screening visit; the recall period for completingthe S-STS at the Day 3 telephone interview will be the time period sinceclinic check-in. The total score plus the subject's response to eachitem will be recorded.

For each administration of the S-STS, the investigator will immediatelyevaluate a subject with any response greater than zero to determine ifthat subject is at risk of self-harm or suicide. If this is the case,the investigator must take appropriate measures to ensure the subject'ssafety and arrange for an appropriate mental health evaluation.

Any subject with a response greater than zero to any question atscreening must be excluded.

At clinic check-in, any subject with a response greater than zero to anyquestion other than Question 2 must be discontinued from the study andthe event recorded as an AE, not treatment-emergent. Subjects with aresponse of 1 (“a little”) to Question 2 will be discontinued at thediscretion of the investigator. Subjects with a response greater than 1on Question 2 will be discontinued.

In case of any response greater than zero at the Day 3 telephoneinterview, the investigator will immediately evaluate that subject todetermine if that subject is at risk of self-harm or suicide. If this isthe case the investigator will take appropriate measures to ensure thesubject's safety and arrange for an appropriate mental healthevaluation. The event will be recorded as a treatment-emergent AE andreported to Svneos Health Safety and Pharmacovigilance within 24 hours.

Measures of Clinical Course (Exploratory Evaluations)

Headache pain and associated migraine symptoms (nausea/vomiting,photophobia, and phonophobia) will be recorded as migraine-relatedevents.

Headache pain will be rated on a 4-point Likert scale (0=none, 1=mild,2=moderate, 3=severe). Associated migraine symptoms (nausea/vomiting,photophobia, and phonophobia) will be classified as either present orabsent.

Migraine-related events observed during the clinic stay will be recordedstarting at the (clock) time of the 10-minute predose migraineevaluation and will be updated at the protocol-specified migraineassessment times (1 hour, 2 hours, 4 hours after dosing, and at cliniccheck-out.

The course of any migraine-related events that are ongoing at clinicdischarge will be followed up at the Day 2 (between 24 and 32 hoursafter dosing) and Day 3 (between 48 and 56 hours after dosing) telephoneinterviews. Any migraine-related event that is newly emergent afterclinic discharge will be recorded and followed up until the Day 3telephone interview. The time course of migraine-related events afterdischarge from the clinic will be based on the subject's bestrecollection of events as reported at the telephone interviews.

The assessment of migraine-related events during the clinic stay and atthe follow-up telephone interviews should begin with a non-leadingquestion (without specific prompting) such as, “How are you doing?” AnyAEs reported by the subject should be recorded.

Structured interview questions are used for assessing headache pain andmigraine-related symptoms at screening, headache onset, clinic check-in,within 10 minutes before dosing, postdose, and at the follow-uptelephone interviews

Statistical Considerations

Safety and Tolerability

Safety and tolerability data will be reported using descriptivestatistics. Summary statistics for TEAEs will be reported. Changes frombaseline values in vital signs, ECG, and clinical laboratory parameterswill be reported.

PK

Interim bioanalysis and PK analyses for fospropofol and propofol are tobe performed after approximately 10 subjects have been completed, againafter approximately 30 subjects are completed, and may be performed atother intervals as well.

Summary statistics will be used to describe the PK profile of bothfospropofol and propofol. Summary statistics will include at minimumarithmetic and geometric means for AUC0-t. AUC0-inf, and Cmax. Tmax willbe characterized by median and range.

Exploratory Analyses

Clinical Course

Summary statistics of the subject's assessment of headache pain (on theLikert scale) at clinic check-in, within 10 minutes predose (baseline),1, 2, and 4 hours postdose, at clinic discharge, and at follow-up onDays 2 and 3 will be reported. Summary statistics of headache recurrenceor worsening will also be reported.

Summary statistics of the subject's assessment of the most bothersomesymptom (presence or absence) at 1, 2, and 4 hours postdose, at clinicdischarge, and at follow-up on Days 2 and 3 will be reported. Summarystatistics of recurrence or worsening of the most bothersome symptomwill also be reported.

Summary statistics of the subject's assessment of migraine-associatedsymptoms other than the most bothersome symptom as applicable (presenceor absence) at 1, 2, and 4 hours postdose, at clinic discharge, and atfollow-up on Days 2 and 3 will be reported. Summary statistics regardingrecurrence or worsening of migraine-associated symptoms will also bereported.

Summary statistics reported will include but not be limited to (1)proportion of subjects reporting no headache pain at 2 hours; (2)proportion of subjects reporting the absence of most bothersome symptomat 2 hours; (3) proportion of subjects reporting improvement in pain(change from severe/moderate to mild/absent) at 2 hours; and (4)durability of responses over 24 and 48 hours regarding freedom fromheadache pain, absence of most bothersome symptom, and improvement inheadache pain. All analyses will be exploratory.

Influence of Covariates; PK-PD Relationships

Exploratory analyses will be performed in an effort to characterize theinfluence of covariates on PK (e.g., relationship between plasmapropofol concentrations and gender, age, weight, and BMI) and tocharacterize PK-PD relationships (e.g., relationship between plasmapropofol concentrations and AEs). Exploratory analyses will also beperformed in an effort to characterize the relationship between plasmapropofol concentration (e.g., Cmax and or partial AUC) and the clinicalcourse of migraine symptoms.

Analytical Methodology

Samples will be transported to the bioanalytical facility packed onsufficient dry ice to keep them frozen for at least 72 hours.

Fospropofol and propofol concentrations will be analyzed in plasmasamples using a validated method.

The bioanalytical work in support to the study will be conducted incompliance with GCP using the SOPs in place in the bioanalyticallaboratory of Syneos Health. Those SOPs were written in accordance withthe current regulations and guidelines in place for industry, includingguidances on Bioanalytical Method Validation, Good Laboratory Practice(GLP) for Nonclinical Laboratory Studies, and Good Clinical Practice(GCP) International Conference on Harmonisation (ICH) E6(R2). US Foodand Drug Administration. Bioanalytical Method Validation: Guidance forIndustry. 2018. Available athttps://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf.US 21 CFR Part 58. Good Laboratory Practice for Nonclinical LaboratoryStudies. Available athttps://www.ecfr.gov/cgi-bin/text-idx?SID=3be49f31878d0efa85f39ed3b84fcbe1&mc=true&node=se21.1.58_11&rgn=div8.US Food and Drug Administration. E6(R2) Good Clinical Practice:IntegratedAddendum to ICH E6(R1) Guidance for Industry. 2018. Availableat https://www.fda.gov/media/93884/download.

Data Handling

All clinical raw data will be recorded promptly, accurately, andlegibly, either as e-source data or indelibly on paper. All raw datawill be conserved in order to maintain data integrity. The investigatorand/or the clinical staff have the responsibility of ensuring thecompleteness and accuracy of the clinical data.

All laboratory results provided by the biomedical laboratory will bestored in an information management system that is a validated Code ofFederal Regulations (CFR) Part 11 compliant application.

Some of the tables below pertain to 12 subjects (N=12) and some pertainto 18 subjects (N=18). The subjects in the N=12 tables are subjects forwhom pharmacokinetic data has been obtained. The subjects in the N=18tables are subjects for whom clinical data has been obtained, andinclude the subjects of the N-12 tables.

TABLE 17-1 Study A17 - Demographic Data Table 17-1 Migraine SubjectCharacteristics (N = 12) Subject Height Weight No. Age Sex (cm) (kg) BMI04-002 42.0 F 156.2 57.2 23.44 04-005 46.0 F 163.5 73.7 27.57 06-00141.0 F 172.7 56.2 18.84 06-002 46.0 F 162.0 59.8 22.79 06-008 42.0 M187.0 103.9 29.71 08-001 51.0 F 163.2 78.7 29.55 08-002 25.0 F 167.482.6 29.48 10-001 45.0 F 156.0 60.6 24.90 11-002 29.0 F 158.8 54.8 21.7312-003 41.0 F 154.8 62.8 26.21 12-005 19.0 F 158.5 68.9 27.43 12-00823.0 F 164.6 57.3 21.15

TABLE 17-1A Summary of Demographic Characteristics of Subjects Treated N= 18 Age (years) n 18 Mean (SD) 38.7 (9.9) Median 41 Min, Max 19, 53 Agegroup (years), n (%) 18-35 6 (33.3) 36-45 7 (38.9) >45 5 (27.8) Sex, n(%) Male 4 (22.2) Female 14 (77.8) Race, n (%) White 11 (61.1) Black orAfrican American 4 (22.2) Asian 1 (5.6) Mixed (Black/White or 2 (11.1)Black/American Indian or Alaska Native) Ethnicity, n (%) Hispanic orLatino 3 (16.7) Not Hispanic or Latino 15 (83.3) Note: Percentages arecalculated as n/N*100. Age was derived using date of birth.

TABLE 17-1B Body Weight and BMI of Subjects Treated N = 18 Weight (kg) n18   Mean (SD) 64.3 (8.2) Median 60.6 Min, Max  54, 82.6 BMI (kg/m2) n18   Mean (SD) 25.0 (3.3) Median 24.8 Min, Max 18.8, 29.71 Note: BMI =Body Mass Index; n = number of subjects; Min = minimum: Max = maximum;SD = Standard Deviation. Percentages are calculated as n/N*100.

TABLE 17-2 Efficacy Results with Propofol Pharmacokinetics (N = 12) TimeTable 1 hr 17-2 Pre-Dose Conc. AUC Subject Headache 1 hr 1 hr HeadacheMBS No. Pain level MBS Type ng/hr ng · h/mL Pain level (Y/N) 4002 SeverePhotophobia 22 21.34 Severe Yes 4005 Severe Photophobia 103.760 59.39Mild Yes 6001 Moderate Phonophobia 302.040 187.95 Mild No 6002 [a]Severe Nausea 513.450 285.41 None Yes 6008 Severe Photophobia 0.000 0.00Moderate Yes 8001 Moderate Photophobia 92.380 52.07 Moderate Yes 8002Severe Photophobia 114.690 199.02 Moderate Yes 10001 ModeratePhotophobia 347.810 177.94 Mild Yes 11002 [a] Moderate Photophobia95.340 60.99 Mild No 12003 Moderate Photophobia 158.790 114.22 ModerateYes 12005 Severe Nausea 55.810 33.03 Moderate Yes 12008 SeverePhotophobia 163.550 130.59 Mild No Time Table 2 hr 4 hr 17-2 Conc. AUCConc. AUC Headache Subject 2 hr 2 hr Headache MBS 4 hr 4 hr Pain MBS No.ng/hr ng · h/mL Pain level (Y/N) ng/hr ng · h/mL level (Y/N) 4002 25.0744.87 Moderate No 79.02 148.96 Moderate No 4005 40.53 131.54 None No13.07 185.14 None No 6001 248.05 462.99 Mild No 46.65 757.69 Mild No6002 [a] 94.42 589.35 None No 27.44 711.21 None No 6008 0 0.00 Mild No3.96 3.96 None No 8001 108.65 152.58 Moderate Yes 47.39 308.62 Mild No8002 63.28 288.01 Mild Yes 27.40 378.69 None No 10001 255.33 479.51Moderate Yes 68.21 803.05 None Yes 11002 [a] 89.48 153.40 Mild No 24.41267.29 Mild No 12003 159.75 273.49 Mild Yes 41.17 474.41 Mild [b] Yes[b] 12005 75.78 98.83 Mild No 36.55 211.16 None No 12008 233.85 329.29None No 97.84 660.98 None No

TABLE 17-2A Co-primary Measures: Freedom from Migraine Headache Pain andFreedom from Most Bothersome Symptom (MBS) at 2 Hours Postdose inSubjects Treated (N = 18) (N = 18) n(%) Freedom from migraine headachepain at 2 hours ¹ Yes 4 (22.2) No 14 (77.8) Freedom from MBS at 2 hours² Yes 12 (66.7) No 6 (33.3) Freedom from both migraine headache pain andMBS at 2 hours Yes 4 (22.2) No 14 (77.8) ¹ Freedom from migraineheadache pain at 2 hours is defined as reduction in headache severityfrom moderate or severe pain within 10 minutes before dosing to no painat 2 hours postdose. A subject is not counted as being pain free if heor she received in-clinic rescue medication at or before the 2-hourassessment. ² Freedom from MBS at 2 hours is defined as absence of themigraine related symptom (nausea/vomiting, phonophobia, or photophobia)that was identified within 10 minutes predose as the most bothersomesymptom. A subject is not counted as being MBS free if he or shereceived in-clinic rescue medication at or before the 2-hour assessment.

TABLE 17-2B Severity of Migraine Headache Pain by Assessment Time Pointin Subjects Treated N = 18 Severity of n (%) ¹ Time point headache painNo rescue ² Rescue ³ Total Within 10 Pain free 0 . . . 0 min predoseMild pain 0 . . . 0 Moderate pain 8 (44.4) . . . 8 (44.4) Severe pain 10(55.6) . . . 10 (55.6) 1 hr postdose Pain free 1 (5.6) 0 1 (5.6) Mildpain 9 (50.0) 0 9 (50.0) Moderate pain 6 (33.3) 0 6 (33.3) Severe pain 2(11.1) 0 2 (11.1) 2 h postdose Pain free 4 (22.2) 0 4 (22.2) Mild pain11 (61.1) 0 11 (61.1) Moderate pain 3 (16.7) 0 3 (16.7) Severe pain 0 00 4 h postdose Pain free 10 (55.6) 2 (11.1) 12 (66.7) Mild pain 4 (22.2)1 (5.6) 5 (27.8) Moderate pain 1 (5.6) 0 1 (5.6) Severe pain 0 0 0Discharge Pain free 12 (66.7) 2 (11.1) 14 (77.8) Mild pain 2 (11.1) 1(5-6) 3 (16.7) Moderate pain 0 0 0 Severe pain 0 0 0 Missing data 1(5.6) 0 1 (5.6) 24 h Pain free 13 (72.2) 0 13 (72.2) postdose (D 2) ⁴Mild pain 3 (16.7) 0 3 (16.7) Moderate pain 1 (11.1) 1 (11.1) 2 (22.2)Severe pain 0 0 0 48 h Pain free 15 (83.3) 0 15 (83.3) postdose (D 3) ⁵Mild pain 0 1 (11.1) 1 (11.1) Moderate pain 0 2 (22.2) 2 (22.2) Severepain 0 0 0 ¹ Percentages are calculated as n/N *100. ² Subjects who didnot receive in-clinic rescue medication pain between administration ofstudy drug and the specified postdose assessment time point or subjectswho did not take medication for acute migraine during the specifiedfollow-up period. ³ Subjects who received in-clinic rescue medicationfor headache pain between administration of study drug and the specifiedassessment time point or who took medication for acute migraine duringthe specified follow-up period. ⁴ Events during the period betweendischarge and the 24-hour follow-up phone call, including headache painpresent at clinic discharge lasting for at least part of the 24-hourperiod after discharge or any episode of headache pain between dischargeand the 24-hour interview, regardless of duration. Severity is definedas the worst pain during the period from discharge to the 24-hourinterview. ⁵ Events during the period between the 24-hour follow-upphone call and the 48-hour follow-up phone call, including any headachepain present at the 24-hour follow-up phone call and lasting for atleast part of the period between the 24-hour and 48-hour follow-up phonecalls. Severity is defined as the worst pain during the period fromdischarge to the 24-hour interview.

TABLE 17-2C Most Bothersome Symptom (MBS) by Time Point in SubjectsTreated N = 18 n (%) ¹ Time point No rescue ² Rescue ³ Total Within MBS18 (100) 0 18 (100) 10 min identified ⁴ predose 1 hr MBS free 7 (38.9) 07 (38.9) post dose MBS present 11 (61.1) 0 11 (61.1) 2 h MBS free 12(66.7) 0 12 (66.7) post dose MBS present 6 (333) 0 6 (33.3) 4 h MBS free14 (77.8) 2 (11.1) 16 (88.9) post dose MBS present 0 2 (11.1) 2 (11.1)Discharge MBS free 13 (72.2) 3 (16.7) 16 (88.9) MBS present 0 0 Datamissing 0 2 (11.1) 2 (11.1) 24 h postdose MBS free 13 (72.2) 2 (11.1) 15(83.3) (Day 2) ⁵ MBS present 0 0 Data missing 0 3 (16.7) 3 (16.7) 48 hpostdose MBS free 12 (66.7) 2 (11.1) 14 (77.8) (Day 3) ⁶ MBS present 0 0Data missing 0 4 (22.2) 4 (22.2) ¹ Percentages are calculated as n/N*100. ² Subjects who did not receive in-clinic rescue medication forheadache pain between administration of study drug and the specifiedpostdose assessment time point or subjects who did not take medicationfor acute migraine during the specified follow-up period. ³ Subjects whoreceived in-clinic rescue medication for headache pain betweenadministration of study drug and the specified assessment time point orwho took medication for acute migraine during the specified follow-upperiod. ⁴ Each subject's individual most bothersome symptom(nausea/vomiting, photophobia, or phonophobia) was identified within 10minutes before dosing with fospropofol disodium. ⁵ Events during theperiod between discharge and the 24-hour follow-up phone call, includingMBS present at clinic discharge lasting for at least part of the 24-hourperiod after discharge or any MBS episode between discharge and the24-hour interview, regardless of duration. ⁶ Events during the periodbetween the 24-hour follow-up phone call and the 48-hour follow-up phonecall, including any MBS present at the 24-hour follow-up phone call andlasting for at least part of the period between the 24-hour and 48-hourfollow-up phone calls.

TABLE 17-2D Sustained Headache Pain Freedom and Sustained Pain ReliefFrom 2 to 24 Hours and From 2 to 48 Hours After Dosing in SubjectsTreated N = 18 n (%) 2-24 hours 2-48 hours postdose postdose Sustainedheadache pain freedom ¹ Yes 4 (22.2) 3 (16.7) No 14 (77.8) 15 (83.3)Sustained headache pain relief ² Yes 12 (66.7) 11 (61.1) No 6 (33.3) 7(38.9) Sustained MBS-free response ³ Yes 10 (55.6) 9 (50) No 8 (44.4) 9(50) ¹ Sustained headache pain freedom is defined as pain freedom ateach assessment from 2 to 24 hours postdose (Day 2 Follow-up) or from 2to 48 hours postdose (Day 3 Follow-up) with no use of in-clinic rescuemedication or medication for acute treatment of migraine after clinicdischarge. ² Sustained headache pain relief is defined as reduction inheadache severity from moderate or severe pain to mild or no headache ateach assessment from 2 to 24 hours postdose (Day 2 Follow-up) or from 2to 48 hours postdose (Day 3 Follow-up) with no use of in-clinic rescuemedication or medication for acute treatment of migraine after clinicdischarge. ³ A sustained MBS-free response is defined as freedom fromthe subject's individual most bothersome symptom (identified predose) ateach assessment from 2 to 24 hours postdose (Day 2 Follow-up) or from 2to 48 hours postdose (Day 3 Follow-up) with no use of in-clinic rescuemedication or medication for acute treatment of migraine after clinicdischarge.

TABLE 17-3 Propofol Pharmacokinetics (N = 12) Subject Cmax Tmax AUC1AUC2 AUC4 Fe- No. ng/mL hr ng · h/mL ng · h/mL ng · h/mL male 4002 79.024 21.34 44.87 148.96 1 4005 103.76 1 59.39 131.54 185.14 1 6001 302.04 1187.95 462.99 757.69 1 6002 513.45 1 285.41 589.35 711.21 1 6008 3.86 40.00 0.00 3.96 0 8001 108.65 2 52.07 152.58 308.62 1 8002 368.56 0.667199.02 288.01 378.69 1 10001 347.81 1 177.94 479.51 803.05 1 11002105.27 0.667 60.99 153.40 267.29 1 12003 159.75 2 114.22 273.49 474.41 112005 75.78 2 33.03 98.83 211.16 1 12008 239.5 0.667 130.59 329.29660.98 1 Mean 200.62 1.67 110.16 250.32 409.26 SD 152.92 1.21 87.40186.30 267.64 CV (%) 76.2% 72.4% 79.3% 74.4% 65.4%

TABLE 17-4 Propofol Pharmacokinetics - (excluding as an outlier datafrom Subject 6008 who exhibited zero or negligible propofol plasmalevels) Subject Cmax Tmax AUC1 AUC2 AUC4 Fe- No. ng/mL hr ng · h/mL ng ·h/mL ng · h/mL male 4002 79.02 4 21.34 44.87 148.96 1 4005 103.76 159.39 131.54 185.14 1 6001 302.04 1 187.95 462.99 757.69 1 6002 513.45 1285.41 589.35 711.21 1 6008 0 8001 108.65 2 52.07 152.58 308.62 1 8002368.56 0.667 199.02 288.01 378.69 1 10001 347.81 1 177.94 479.51 803.051 11002 105.27 0.667 60.99 153.40 267.29 1 12003 159.75 2 114.22 273.49474.41 1 12005 75.78 2 33.03 98.83 211.16 1 12008 239.5 0.667 130.59329.29 660.98 1 Mean 218.51 1.45 120.18 273.08 446.11 SD 146.62 1.0084.14 177.03 246.73 CV (%) 67.1% 68.9% 70.0% 64.8% 55.3%

TABLE 17-5 Ratio of Mean Propofol Pharmacokinetics - Migraine subjectsvs. Healthy Volunteers (Study A17 vs. Study A16 (800 mg Cohort from A16,excluding subject 308)). Ratio of mean values in migraine subjects tohealthy volunteers Cmax Tmax Auc1 Auc2 Auc4 87% 77% 89% 95% 106%

TABLE 17-6 Ratio of Mean Propofol Pharmacokinetics - Migraine subjectsvs. Healthy Volunteers - Females (Study A17 vs. Study A16 (800 mg Cohortfrom A16, females only). Ratio of mean values in migraine subjects (allfemale) to female healthy volunteers Cmax Tmax Auc1 Auc2 Auc4 80% 66%85% 85% 91%

Table 17-7 - Efficacy Results with Fospropofol Pharmacokinetics (N=12)Time Table 1 hr 17-7 Pre-Dose Conc. AUC Subject Headache 1 hr 1 hrHeadache MBS No. Pain level MBS Type ng/hr ng · h/mL Pain level (Y/N)4002 Severe Photophobia 327.410 723.61 Severe Yes 4005 SeverePhotophobia 1146.030 2418.57 Mild Yes 6001 Moderate Phonophobia 2525.1005268.76 Mild No 6002 [a] Severe Nausea 2369.220 6456.6 None Yes 6008Severe Photophobia 0.00 0.00 Moderate Yes 8001 Moderate Photophobia1791.790 2684.78 Moderate Yes 8002 Severe Photophobia 162.560 1315.43Moderate Yes 10001 Moderate Photophobia 1697.140 3262.09 Mild Yes 11002[a] Moderate Photophobia 1302.040 3522.27 Mild No 12003 ModeratePhotophobia 1818.430 5673.87 Moderate Yes 12005 Severe Nausea 741.1501193.95 Moderate Yes 12008 Severe Photophobia 3342.040 4461.52 Mild NoTime Table 2 hr 4 hr 17-7 Conc. AUC Conc. AUC Subject 2 hr 2 hr HeadacheMBS 4 hr 4 hr Headache MBS No. ng/hr ng · h/mL Pain level (Y/N) ng/hr ng· h/mL Pain level (Y/N) 4002 240.76 1007.69 Moderate No 0.00 1248.45Moderate No 4005 107.28 3045.22 None No 0.00 3152.5 None No 6001 399.276730.95 Mild No 0.00 7130.22 Mild No 6002 [a] 230.24 7756.33 None No0.00 7986.57 None No 6008 0.00 0.00 Mild No 0.00 0.00 None No 8001170.91 3666.13 Moderate Yes 0.00 3837.04 Mild No 8002 48.78 1421.1 MildYes 0.00 1469.88 None No 10001 128.44 4174.88 Moderate Yes 0.00 4303.32None Yes 11002 [a] 427.36 4386.97 Mild No 0.00 4814.33 Mild No 12003239.76 6702.97 Mild Yes 0.00 6942.73 Mild [b] Yes [b] 12005 91.971610.51 Mild No 0.00 1702.48 None No 12008 1626.55 6945.81 None No 0.008572.36 None No

TABLE 17-8 Fospropofol Pharmacokinetics (N = 12) Subject Cmax Tmax AUC1AUC2 AUC4 Fe- No. ng/mL hr ng · h/mL ng · h/mL ng · h/mL male 40021419.1 0.333 723.61 1007.69 1248.45 1 4005 4507.39 0.333 2418.57 3045.223152.5 1 6001 11463.93 0.333 5268.76 6730.95 7130.22 1 6002 10001.180.167 6456.6 7756.33 7986.57 1 6008 0 0 0 0 0 8001 5163.62 0.333 2684.783666.13 3837.04 1 8002 3285.03 0.333 1315.43 1421.1 1469.88 1 100015036.79 0.167 3262.09 4174.88 4303.32 1 11002 7527.26 0.333 3522.274386.97 4814.33 1 12003 10597.13 0.333 5673.87 6702.97 6942.73 1 120052219.93 0.667 1193.95 1610.51 1702.48 1 12008 8307.86 0.333 4461.526945.81 8572.36 1 Mean 5794.10 0.33 3081.79 3954.05 4263.32 SD 3773.680.13 2074.98 2629.28 2879.02 CV (%) 65.1% 38.7% 67.3% 66.5% 67.5%

TABLE 17-9 Fospropofol Pharmacokinetics (Fospropofol plasmaconcentrations in Subject 6008 were zero (below limit of quantitation)at all time points) Subject Cmax Tmax AUC1 AUC2 AUC4 Fe- No. ng/mL hr ng· h/mL ng · h/mL ng · h/mL male 4002 1419.1 0.333 723.61 1007.69 1248.451 4005 4507.39 0.333 2418.57 3045.22 3152.5 1 6001 11463.93 0.3335268.76 6730.95 7130.22 1 6002 10001.18 0.167 6456.6 7756.33 7986.57 16008 0 8001 5163.62 0.333 2684.78 3666.13 3837.04 1 8002 3285.03 0.3331315.43 1421.1 1469.88 1 10001 5036.79 0.167 3262.09 4174.88 4303.32 111002 7527.26 0.333 3522.27 4386.97 4814.33 1 12003 10597.13 0.3335673.87 6702.97 6942.73 1 12005 2219.93 0.667 1193.95 1610.51 1702.48 112008 8307.86 0.333 4461.52 6945.81 8572.36 1 Mean 6320.84 0.33 3361.954313.51 4650.90 SD 3464.45 0.13 1923.55 2428.76 2671.10 CV (%) 54.8%38.7% 57.2% 56.3% 57.4%

TABLE 17-10 Ratio of Mean Fospropofol Pharmacokinetics - Migrainesubjects vs. Healthy Volunteers (Study A17 vs. A16). Ratio of meanvalues in migraine subjects (Study A17) to healthy volunteers (800 mgCohort from A16, excluding subject 308) Cmax Tmax Auc1 Auc2 Auc4 105%98% 121% 130% 135%

TABLE 17-11 Ratio of Mean Fospropofol Pharmacokinetics - Migrainesubjects vs. Healthy Volunteers (Study A17 vs. A16). Ratio of meanvalues in migraine subjects (all female; from A17) to female healthyvolunteers (800 mg Cohort from A16, excluding subject 308) Cmax TmaxAuc1 Auc2 Auc4 94% 89% 110% 116% 120%

Systemic Exposure to Propofol after Administration of FospropofolDisodium to Subjects with Migraine is Inversely Related to Time toTreatment

Fospropofol Disodium, 800 mg, was administered orally under medicalsupervision to 12 adult subjects in the course of a migraine episode(within 4 hours of the reported onset of migraine symptoms). Subjectsreported time of onset of migraine symptoms and the time intervalbetween onset of symptoms and treatment with Fospropofol Disodium(time-to-treatment) was recorded. Plasma concentrations of fospropofoland propofol were measured predose and at intervals until 4 hours afterdosing. The potential influence of a variety of covariates on systemicexposure (maximal plasma concentration [C_(max)] and area under theplasma concentration curve at 1, 2, and 4 hours [AUC1, AUC2, AUC4]) forboth fospropofol and propofol was examined. One of 12 migraine subjectswho exhibited negligible plasma concentrations for both fospropofol andpropofol was excluded from analysis. Values for Cmax and AUCs werelog-transformed. Time to treatment among the migraine subjects rangedfrom 115 to 230 minutes.

Among the 11 migraine subjects in the analysis (all female), there was astatistically significant inverse association between time-to-treatmentand log propofol Cmax (p=0.007), log propofol AUC 1 (p=0.004), logpropofol AUC2 (p=0.009), and log propofol AUC4 [FIGS. 18, 20, 22, 24 ].A similar trend (not statistically significant) toward an inverseassociation between time-to-treatment and fospropofol exposure wasobserved for log fospropofol Cmax (p=0.067) and log fospropofol AUC1(p=0.98) [FIGS. 17 and 19 ]. The statistically significant inverseassociation between propofol exposure and time-to-treatment wasunchanged after adjustment for other covariates including age, weight,BMI, and reported time since last meal. Time-to-treatment accounted for˜57%, 63%, 55%, and 40% of the variability in propofol log Cmax,propofol log AUC1, propofol log AUC2, and propofol log AUC4,respectively [FIGS. 18, 20, 22, 24 ]. Beta coefficients from the linearregressions [FIGS. 18, 20, 22, 24 ] indicate that over the observedtime-to-treatment interval, geometric mean [GM] propofol C_(max)decreased by 1.45% per minute of delay in time-to-treatment (58.5% perhour); GM propofol AUC1 decreased by 1.84% per minute (67.2% per hour);GM propofol AUC2 decreased by 1.62% per minute (62.5% per hour); and GMpropofol AUC4 decreased by 1.08% per minute (47.7% per hour).

To explore whether the bioavailability of propofol relative tofospropofol was inversely associated with time to treatment, the log ofthe ratio of AUC1 propofol to AUC1 fospropofol and the log of the ratioof AUC2 propofol to AUC2 fospropofol were used as approximate indicatorsof the relative bioavailability at 1 and 2 hours after dosing [FIGS. 25and 26 ]. There was a trend (not statistically significant) toward aninverse association of time-to-treatment with the log of the ratio ofAUC1 propofol to AUC1 fospropofol (p=0.141) and the log of the ratio ofAUC2 propofol to AUC2 fospropofol (p=0.157) [FIGS. 25 and 26 ]. Acomparison of the log of the ratio of AUC1 propofol to AUC1 fospropofolbetween the 11 migraine subjects and 9 healthy volunteers who receivedFospropofol Disodium, 800 mg indicated that the distribution of the logof the ratio of AUC1 propofol to AUC1 fospropofol was different betweenmigraine subjects and healthy volunteers, p=0.0367 (Wilcoxon rank-sumtest).

TABLE 17-12A All TEAEs by SOC and PT in Subjects Treated (N = 18)MedDRA ® System Organ Class N = 18 MedDRA ® Preferred Term n (%) ENumber of subjects with at least 1 TEAE, n (%) 6 (33.3) Number of TEAEs,E 9 Nervous system disorders 3 (16.7) 4 ¹ Somnolence 1 (5.6) 1Paraesthesia ² 2 (11.1) 2 Dysgeusia 1 (5.6) 1 Reproductive system andbreast disorders 1 (5.6) 2 Genital paraesthesia ² 1 (5.6) 2 Skin andsubcutaneous tissue disorders 1 (5.6) 1 Pruritus ² 1 (5.6) 1Gastrointestinal disorders 2 (11.1) 2 Nausea 1 (7.7) 1 Dry mouth 1 (7.7)1 E = number of TEAEs; N = number of subjects dosed; n (%): number andpercent of subjects with TEAE; MedDRA ® = Medical Dictionary forRegulatory Activities, Version 24.0; TEAEs = treatment-emergent adverseevents. Each subject could only contribute once to each of the incidencerates, regardless of the number of occurrences; the highest severity ispresented. ¹ One subject had paraesthesia, dysgeusia, and dry mouth. ²Paresthesia and pruritus are known adverse reactions associated withintravenous fospropofol. (Prescribing information for LUSEDRA ™[fospropofol disodium] Injection, for intravenous use. Revised October2009. Available athttps://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022244s006lb1.pdf)

TABLE 17-12B Severity of TEAEs by SOC and PT in Subjects Treated (N =18) N = 18 MedDRA ® System Organ Class n (%) MedDRA ® Preferred TermMild Moderate Severe Number of subjects with at least 1 TEAE 3  3¹  1¹Number of TEAEs, E 5 3 1 Nervous system disorders 3 1 0 Somnolence 1 0 0Paraesthesia 1 1 0 Dysgeusia 1 Reproductive system and breast disorders0  1¹  1¹ Genital paraesthesia 0  1¹  1¹ Number of subjects with atleast 1 TEAE 3  3¹  1¹ Skin and subcutaneous tissue disorders 1 0 0Pruritus 1 0 0 Gastrointestinal disorders 1 1 0 Nausea 0 1 0 Dry mouth 10 0 MedDRA ® = Medical Dictionary for Regulatory Activities, Version24.0; TEAEs = treatment-emergent adverse events. ¹Two AEs in the samesubject (Genital paraesthesia initially rated severe and subsequentlymoderate)

TABLE 17-12C Relation of TEAEs to Study Drug by SOC and PT in SubjectsTreated (N = 18) N = 18 n (%) MedDRA ® System Organ Class PossiblyProbably MedDRA ® Preferred Term related related Number of TEAEs, E 2 7Nervous system disorders 0 4 Somnolence 0 1 Paraesthesia¹ 0 2 Dysgeusia0 1 Reproductive system and breast disorders 0 2 Genital paraesthesia¹ 02 Skin and subcutaneous tissue disorders 1 0 Pruritus¹ 1 0Gastrointestinal disorders 1 1 Nausea 1 Dry mouth 0 1 MedDRA ® = MedicalDictionary for Regulatory Activities, Version 24.0; TEAEs =treatment-emergent adverse events. ¹Paresthesia and pruritus are knownadverse reactions associated with intravenous fospropofol. (Prescribinginformation for LUSEDRA ™ [fospropofol disodium] Injection, forintravenous use. Revised October 2009. Available athttps://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022244s006lb1.pdf)

Example 18, Study A18

Single-Dose, Open-Label, PK and Safety-Tolerability 2-Sequence, 3-PeriodCrossover Study of FOSPROPOFOL DISODIUM TABLETS (200-mg strength)Compared to the FOSPROPOFOL DISODIUM CAPSULE (200-mg strength) inHealthy Male and Female Adults Under Fasting Conditions with Evaluationof the Tablet Food Effect

-   -   Study Drugs Fospropofol Disodium capsule (200-mg strength),        Fospropofol Disodium tablet (200-mg strength)    -   Study Phase and Type Phase 1        -   Part 1: Open-label, single-dose pilot study (Single 200-mg            tablet)        -   Part 2: Open-label, randomized 2-sequence, 3-period,            3-treatment crossover. Treatments Fospropofol Disodium            200-mg capsules fasted [4 capsules]; Fospropofol Disodium            tablets 200 mg fasted [number of tablets TBD]; Fospropofol            Disodium tablets 200 mg after a high fat meal [number of            tablets TBD—same as (B)] (D) Optional Fospropofol Disodium            tablets 200 mg after a moderate fat meal [number of tablets            TBD—same as (B) and (C)]    -   Objectives Primary Objectives        -   To assess the safety-tolerability and pharmacokinetics (PK)            of fospropofol and propofol following a single 200 mg dose            of the Fospropofol Disodium tablet administered under            fasting conditions to healthy adult male and female            volunteers.        -   To assess the safety-tolerability and comparative            pharmacokinetics (PK) including PK variability of            fospropofol and propofol following single doses of            Fospropofol Disodium administered orally (p.o.) to healthy            adult male and female volunteers as (A) Fospropofol Disodium            200 mg capsules fasted [four capsules] (B) Fospropofol            Disodium tablets 200 mg fasted [number of tablets TBD] (C)            Fospropofol Disodium tablets 200 mg after a high fat meal            [number of tablets TBD—same as (B)](D) Optional: Fospropofol            Disodium tablets 200 mg after a moderate fat meal [number of            tablets TBD—same as (B) and (C)]    -   Study Design A single-center, Phase 1 PK and safety-tolerability        study in 2 parts. Part 1 is a pilot study of the PK profile        (fospropofol and propofol) after a single dose of the 200 mg        Fospropofol Disodium tablet.        -   Part 1 will comprise a cohort of 12 healthy adult male and            female subjects (at least 50% women). The sample size of 12            subjects is judged sufficient as a pilot study to assess            exposure to propofol with the novel tablet formulation and            the timing of the maximal plasma concentration for each            analyte. Subjects participating in Part 1 will not be            permitted to participate in Part 2 of the study.        -   Although the PK of the Fospropofol Disodium 200 mg capsule            has been well characterized in study A16 after single doses            ranging from 200 to 2000 mg, the Fospropofol Disodium 200 mg            tablet has not been studied in humans. The PK data after            administration of the 200 mg tablet from Part 1 will be used            to determine the dose (number of 200 mg tablets) to be            administered in Part 2 of the study and will also inform the            PK sampling schedule to be used in Part 2.        -   Part 2 is a randomized, 2-sequence, single-dose crossover            comparison of Fospropofol Disodium 200-mg tablets vs            Fospropofol Disodium 200-mg capsules under fasting            conditions, with a third visit for half of the subjects            chosen at random to receive a single dose of Fospropofol            Disodium 200-mg tablets administered after a high-fat meal.            Depending on results after the high-fat meal, a single dose            of Fospropofol Disodium 200-mg tablets may be administered            after a moderate-fat meal. The PK profile will be determined            for fospropofol and propofol after all visits.        -   Part 2 will comprise a separate cohort of 18-24 subjects (at            least 50% women). Fospropofol Disodium 200-mg capsule            administration will consist of 4 capsules (800 mg). The            number of Fospropofol Disodium 200-mg tablets will depend on            the propofol exposure observed after administration of the            200-mg tablet in Part 1.        -   A total of 18-24 subjects will complete the first 2 periods.            It is not required that all 24 subjects enter the clinic as            a single cohort. For example, it may be preferable for these            subjects to be admitted to the clinic as two cohorts of 12.        -   Following the second period, half of the subjects (9-12            subjects) who completed Visits 1 and 2 (selected at random),            will participate in a third visit at which the same dose of            Fospropofol Disodium 200-mg tablets will be administered            after a high-fat meal. Depending on the results of PK            analysis of samples from these subjects, the remaining            subjects (9-12 subjects) will receive the same dose of            Fospropofol Disodium 200-mg tablets after a moderate-fat            meal.        -   The number of tablets to be administered in Part 2 will be            determined based on the PK results after administration of            the 200-mg tablet in Part 1, with the goal of selecting the            number of 200 mg tablets to be that provide a predicted mean            maximal propofol concentration (mean propofol C_(max))            similar or somewhat higher (but not lower) than the mean            propofol C_(max) observed in Study A16 following an 800-mg            dose (4 Fospropofol Disodium 200-mg capsules) administered            to healthy adults under fasting conditions. For purposes of            this prediction, propofol PK will be assumed to be            dose-proportional.    -   Rationale for Dose Selection Part 1:        -   Part 1 will investigate the PK of fospropofol and propofol            after a single tablet of Fospropofol Disodium 200 mg in a            cohort of 12 subjects (including at least 6 women).        -   Extensive Phase 1 single ascending dose study was conducted            with the Fospropofol Disodium 200-mg capsule. A total of 70            healthy adult men and women received single doses ranging            from 200 mg [1 capsule] to 2000 mg [10 capsules]. After a            single 200-mg capsule, propofol C_(max) (arithmetic mean,            n=10) was 69.43 ng/mL, and propofol C_(max) (geometric mean,            n=10) was 61.68 ng/mL. Propofol AUC_(0-inf) (arithmetic            mean, n=10) was 118.08 h*ng/mL, and propofol AUC_(0-inf)            (geometric mean, n=10) was 112.08 h*ng/mL.        -   PK studies in dogs using an experimental 600 mg tablet            acidified with acetic acid or 3 200 mg capsules under fasted            conditions (fasted dogs pretreated with pentagastrin)            indicated that propofol C_(max) (arithmetic mean) was            approximately 44% higher with tablet dosing compared to            capsule dosing and AUC_(0-inf) was approximately doubled            with tablet dosing compared to capsule dosing. If the            enhanced performance of an acidified tablet in man is            similar to that in the dog, the predicted propofol C_(max)            (arithmetic mean) in man following a 200 mg acidified tablet            would be approximately 100 ng/mL and the predicted            AUC_(0-inf) (arithmetic mean) would be approximately 236            h*ng/mL. Propofol exposures of this magnitude were observed            in Study A16 after a capsule dose of 400 mg and these            exposures were well-tolerated.        -   The expected propofol C_(max) in humans following a 200-mg            tablet is well below 1.7 μg/mL (1700 ng/mL), a typical            propofol concentration for conscious sedation, and far below            the propofol plasma concentrations (greater than 2 μg/mL            [2000 ng/mL]) associated with loss of consciousness or            respiratory depression. Oei-Lim V L, White M, Kalkman C J,            Engbers F H, Makkes P C, Ooms W G. Pharmacokinetics of            propofol during conscious sedation using target-controlled            infusion in anxious patients undergoing dental treatment. Br            J Anaesth 1998; 80:324-31.        -   Part 2:        -   The tablet dose (number of 200 mg tablets) to be used in            Part 2 will be selected to provide a predicted mean propofol            C_(max) similar or somewhat higher (but not lower) than the            mean propofol C_(max) observed in Study A16 following an            800-mg dose (4 Fospropofol Disodium 200-mg capsules).        -   After a single dose of 800 mg Fospropofol disodium in Epalex            study Study A16 (administered as four 200 mg capsules)            propofol C_(max) (arithmetic mean, n=10) was 362.01 ng/mL            (range 259.72 to 1352.75 ng/mL). Propofol AUC_(0-inf)            (arithmetic mean, n=10) was 558.93 h*ng/mL (range 535.00 to            1077.32 ng/mL). These exposures were well-tolerated. These            propofol plasma concentrations are below 1.7 μg/mL (1700            ng/mL), a typical propofol concentration for conscious            sedation, and below the propofol plasma concentrations            (greater than 2 μg/mL [2000 ng/mL]) associated with loss of            consciousness or respiratory depression. Thus, it can be            expected that the propofol exposures in Study A18 are well            separated from anesthetic exposures associated with            respiratory depression. Puri GD. Target controlled infusion            total intravenous anaesthesia and Indian patients: Do we            need our own data? Indian J Anaesth 2018; 62:245-8.    -   Sentinel Subjects Because there is no clinical experience with        the Fospropofol Disodium 200 mg tablet, 2 sentinel subjects will        be employed in Part 1 and 4 Sentinel subjects will be employed        in Part 2 of the study.        -   In Part 1, sentinel dosing will be implemented as follows:            The 2 sentinel subjects will be dosed on the same day. If            the dose is judged safe and well-tolerated upon clinical            safety review by the PI, dosing of the remaining 10 subjects            in the cohort can occur (no sooner than 20 hours after            sentinel dosing).        -   In Part 2, sentinel dosing will be used in the first            treatment period for subjects receiving Fospropofol Disodium            tablets under fasting conditions and in the first treatment            period for subjects receiving Fospropofol Disodium tablets            after a meal. For each condition, the 2 sentinel subjects            will be dosed on the same day. Thus, the first set of 2            sentinel subjects will receive Fospropofol Disodium tablets            200 mg fasted [number of tablets TBD], and the second set of            2 sentinel subjects will receive Fospropofol Disodium            tablets 200 mg after a high fat meal [the same number of            tablets administered in the fasting condition]. For each of            these conditions, if the dose is judged safe and            well-tolerated upon clinical safety review by the PI, dosing            of the remaining subjects for that condition can occur (no            sooner than 20 hours after sentinel dosing).    -   Study Population The total number of subjects to be treated in        Part 1 of the study is 12; The total number of subjects to be        treated in Part 2 of the study is 18-24. Thus, a total of 30-36        healthy adult male and female subjects (≥18 and ≤55 years of        age, with a BMI ≥18.5 and ≤29.9 kg/m²) will be treated over the        course of the study.        -   Subjects who withdraw or are withdrawn from the study before            dosing may be replaced. Subjects who withdraw or are            withdrawn from the study after receiving study drug will not            be replaced.    -   Screening Procedures Screening is to occur within 30 days before        administration of study medication. Screening procedures will        include demographic data, medical and medication histories,        complete physical examination, body measurements,        electrocardiogram (ECG), vital signs (blood pressure [BP], heart        rate [HR], respiratory rate [RR], pulse oximetry [PO], and oral        temperature), hematology, blood chemistry, human        immunodeficiency virus (HIV), hepatitis B and C tests,        urinalysis, urine drug screen, alcohol breath test, urine        cotinine test, and urine pregnancy test for women.    -   Confinement and Washout For Part 1 of the study, all 12 subjects        will be confined to the study site for at least 14 hours before        dosing and for at least 10 hours after dosing. However, the        duration of confinement and frequency of monitoring may be        increased for safety reasons.        -   In Part 1 when sentinel subjects are used, 4 sentinel            candidates will be confined to the study site for at least            14 hours before sentinel dosing. Of these, 2 subjects will            be randomly selected as sentinels and 2 will serve as            standby sentinels. Predose safety monitoring procedures will            be the same for sentinel standbys as for chosen sentinels.            The 2 standby subjects not selected as sentinels will            continue confinement in the clinic and will be dosed with            the remaining 8 subjects, no sooner than 20 hours after            dosing of the sentinels (without need for repeating check-in            procedures). Thus, the total confinement period for the            sentinel standby subjects may last approximately 20-24 hours            longer than for the sentinel subjects.        -   In Part 2 of the study a total of 18-24 subjects will be            randomized to one of 2 treatment sequences. Each subject            will receive the tablets and the capsules according to the            assigned treatment sequence. The same procedures for            sentinel subjects used in Part 1 will also be followed in            Part 2.    -   Study Drug and Dosage Form The Fospropofol Disodium capsule 200        mg nominal dose is formulated for oral administration in        hydroxypropyl methylcellulose (HPMC) capsules. Each HPMC capsule        contains 200 mg of fospropofol disodium corrected for water and        no inactive ingredients.        -   The Fospropofol Disodium tablet 200 mg strength is            formulated for oral administration in a tablet. Each tablet            contains 200 mg of fospropofol free acid provided as 230.5            mg of fospropofol disodium corrected for water. The tablet            is acidified with citric acid or with tartaric acid.    -   Study Drug Administration The sequence randomization (assignment        to one of two sequences) will be performed according to a        schedule generated using validated computer software.        -   Study Part 1        -   In Part 1 of the study, a single dose of the Fospropofol            Disodium tablet 200 mg strength will be administered to 12            subjects. Two sentinel subjects will be dosed and observed            for 20 hours before the remaining 10 subjects are treated.            No food will be allowed from at least 10 hours before dosing            until at least 4 hours after dosing.        -   Study Part 2        -   In Part 2, the crossover portion of the study, 24 subjects            will be randomized to one of two treatment sequences. The            sequence randomization will be performed according to a            schedule generated by the CRO using validated proprietary            computer software.        -   In the first period of Part 2, the 2 sentinel subjects            assigned to receive 200-mg Fospropofol Disodium tablets            under fasting conditions (number of tablets TBD) will be            dosed and observed for 20 hours before the remaining the            subjects are treated.        -   In the third period of Part 2, the 2 sentinel subjects            assigned to receive 200-mg Fospropofol Disodium tablets            after a high-fat meal (the same number of tablets as in the            fasting condition [TBD]) will be dosed and observed for 20            hours before the remaining the subjects are treated.        -   For dosing in all conditions, the study drug will be            administered with water at ambient temperature in the amount            of approximately 240 mL [8 oz]. Except for water            administered with study drug, no fluids will be allowed from            1 hour before dosing until 1 hour after dosing.        -   For safety reasons, subjects will be required to remain            seated or semi-reclined and avoid sleeping for 1 hour before            and for the first 4 hours after drug administration.    -   Washout Not applicable to Part 1. Part 2 will employ a washout        period of at least 1 week between dosing days.    -   Inclusion Criteria Subjects must meet all of the following        criteria to be included in the study:        -   1. Male or female        -   a) Nonsmoker (no use of tobacco products within 3 months            prior to screening),        -   b) ≥18 and ≤55 years of age        -   c) BMI ≥18.0 and ≤29.9 kg/m²        -   d) body weight ≥50.0 kg for male and ≥45.0 for female            subjects. 2. Healthy as defined by:        -   e) The absence of clinically significant illness and surgery            within 4 weeks prior to dosing. Subjects with a history of            vomiting will be carefully evaluated. Inclusion of such            subjects is at the discretion of the PI.        -   f) The absence of clinically significant history of            neurological (other than migraine), endocrine,            cardiovascular, pulmonary, hematological, immunologic,            psychiatric, gastrointestinal, renal, hepatic, and metabolic            disease.        -   g) The absence of clinically significant history of sleep            apnea        -   3. Ability to comprehend the nature of the study, as            assessed by the PI or delegate. Capable of giving written            informed consent. Able to communicate effectively with            clinic staff.        -   4. Ability to fast for at least 14 hours and consume            standard meals during the study.        -   5. Availability to volunteer for the entire study duration            and willing to adhere to all protocol requirements.        -   6. Female subjects must agree not to be nursing at any time            during the study and until 30 days after study drug            administration.        -   7. Female subjects must fulfill at least one of the            following:        -   a) Surgically sterile, defined as women who have had a tubal            ligation, hysterectomy, or bilateral oophorectomy at least 6            months prior to drug administration.        -   b) Post-menopausal, defined as absence of menses for at            least 12 months prior to drug administration.        -   c) Women who are sexually active and at risk for pregnancy            must agree to avoid pregnancy and use medically acceptable            method of contraception from at least 30 days prior to            administration of study drug until 30 days after study drug            administration.        -   Medically acceptable methods of contraception include            hormonal contraception, hormonal or non-hormonal            intrauterine device, double barrier method (simultaneous use            of male condom with intravaginally applied spermicide and            diaphragm or cervical cap), or male partner vasectomy at            least 6 months previously. Complete abstinence alone can be            used as a method of contraception.        -   8. Male subjects who are not vasectomized for at least 6            months, and who are sexually active with a non-sterile            female partner (see definitions of surgically sterile and            post-menopausal above) must be willing to use one of the            following acceptable contraceptive methods throughout the            study and for 90 days after the study drug administration:        -   a) Simultaneous use of male condom and, for the female            partner, intrauterine contraceptive device with or without            hormone release (placed at least 4 weeks previously).        -   b) Simultaneous use of male condom and, for the female            partner, hormonal contraception.        -   c) Simultaneous use of male condom and, for the female            partner, intravaginally applied spermicide with diaphragm or            cervical cap.    -   Exclusion Criteria Subjects to whom any of the following applies        will be excluded:        -   1. Any clinically significant abnormality at physical            examination, clinically significant abnormal laboratory test            results or positive serologic test for hepatitis B,            hepatitis C, or HIV found during medical screening.            (Subjects with positive serology for hepatitis C and            negative HCV RNA are eligible at the discretion of the PI.)        -   2. Positive urine drug screen, alcohol breath test, urine            cotinine test at screening (or at clinic check-in)        -   3. For women, positive urine pregnancy test at screening or            positive serum pregnancy test at clinic check-in.        -   4. History of severe allergic reactions (e.g. anaphylactic            reactions, angioedema), hypersensitivity or idiosyncratic            reaction to fospropofol, propofol, excipients or related            substances.        -   5. Individuals having undergone any major surgery within 6            months prior to the start of the study, unless deemed            otherwise by the PI.        -   6. Clinically significant ECG abnormalities (e.g., QTcF>450            msec in males or >470 msec in females) or vital sign            abnormalities (systolic BP lower than 95 or over 140 mmHg,            diastolic BP lower than 55 or over 90 mmHg, or HR less than            50 or over 100 bpm) at screening.        -   7. Oxygen saturation by oximetry less than 93% at screening        -   8. History of significant alcohol abuse within 1 year prior            to screening or regular use of alcohol of more than 14 units            of alcohol per week (1 unit=150 mL of wine, 360 mL of beer,            or 45 mL of 40% alcohol) within 6 months prior to the            screening visit.        -   9. History of significant drug abuse within one year prior            to screening or use of hard drugs (such as cocaine,            phencyclidine [PCP], crack, opioid derivatives including            heroin, and amphetamine derivatives) within 1 year prior to            screening.        -   10. Participation in an interventional clinical research            study involving the administration of an investigational or            marketed drug or device within 30 days prior to            administration of study drug or administration of a            biological product in the context of a clinical research            study within 90 days prior to administration of study drug.            Concomitant participation in an investigational study            involving no drug or device administration is permitted            provided obligations associated with the concomitant            participation are not expected to interfere with procedures            and obligations of the present study.        -   11. Use of medication other than topical products without            significant systemic absorption:        -   a) prescription medication (excluding hormonal            contraception) within 14 days prior to the first dosing;        -   b) over-the-counter products and natural health products            (including herbal remedies such as St. John's wort,            homeopathic and traditional medicines, probiotics, food            supplements such as vitamins, minerals, amino acids,            essential fatty acids, and protein supplements used in            sports) within 7 days prior to the first dosing, with the            exception of the occasional use of acetaminophen (up to 2 g            daily);        -   c) a depot injection or an implant of any drug within 3            months prior to the first dosing, excluding hormonal            contraception.        -   12. Donation of plasma within 7 days prior to dosing.            Donation or loss of blood (excluding volume drawn at            screening) of 50 mL to 499 mL of blood within 30 days, or            more than 499 mL within 56 days prior to the first dosing.        -   13. Hemoglobin <128 g/L (<12.8 g/dL) for men or 115 g/L            (<11.5 g/dL) for women at screening.        -   14. Intolerance to and/or difficulty with blood sampling            through venipuncture.        -   15. Abnormal diet patterns (for any reason) during the 4            weeks preceding the study, including fasting, high protein            diets etc.        -   16. Employee or immediate relative of an employee of Epalex            Corporation, or its affiliates or partners.    -   Study Restrictions Subjects will be asked to refrain from using        products that may potentially affect their safety and/or the PK        of the study drug. Main study restrictions include:        -   Prescription medication (excluding hormonal contraception)            from 14 days prior to dosing until after the last PK blood            sample collection of the study        -   Over-the-counter products from 7 days prior to dosing until            after the last PK blood sample collection of the study        -   Natural health products from 7 days before dosing until            after the last PK blood sample collection        -   Food containing poppy seeds within 24 hours prior to            admission        -   Alcohol-based products from 48 hours prior to dosing until            after the last PK blood sample collection        -   Subjects will be required to abstain from using soft or hard            drugs (including marijuana and tetrahydrocannabinol            (THC)-containing products) or any tobacco or nicotine            products from screening and throughout the study.    -   PK Sampling Time Points In Part 1 of the Study a total of 14        blood samples of 6 ml each will be collected for analysis of        fospropofol and propofol PK. The PK samples will be collected at        the following time points: Predose (within 120 minutes before        dosing) and postdose at 5, 10, 20, 30, and 45 minutes and 1,        1.5, 2, 3, 4, 5, 6, and 9 hours after dosing.        -   In Part 2 of the study a total of 14 blood samples of 6 ml            each will be collected for analysis of fospropofol and            propofol PK.        -   However, the sampling schedule to be used in Part 2 will be            informed by the PK results from Part 1.    -   Safety Monitoring Medical Surveillance and AE Monitoring        Subjects will be monitored throughout the study by clinic staff        for AEs.        -   Subjects should be continuously monitored for early signs of            hypotension, apnea, airway obstruction, and/or oxygen            desaturation. As a precautionary measure, for dosing in Part            1, a person trained in airway management and not involved in            any critical study procedures will be on site to monitor the            subjects from approximately 30 minutes prior to each dosing            and until 9 hours after administration of the study            medication to the last subject.        -   Additionally, the clinic will be staffed and equipped to            manage hypotension, hypoxemia, and airway obstruction and/or            apnea, including cardiac dysrhythmias or bradycardia known            to occur with sedative-hypnotic agents.        -   For both Part 1 and Part 2 of the study, the PI or medically            qualified delegate will be on site approximately 30 minutes            prior to each dosing and until 6 hours after administration            of the study medication to the last subject, and available            on call for the remainder of the study.        -   Continuous Cardiac Telemetry and Pulse Oximetry        -   In Part 1 of the study, to ensure the absence of any            clinically significant cardiac arrhythmia or other            abnormality at baseline (before dosing), cardiac telemetry            will be performed from at least 10 hours before dosing and            will be continued for approximately 6 hours after dosing (or            until clinic discharge, at the Investigator's discretion if            necessary for safety reasons) to monitor for any cardiac            effects of the study drug. Subjects with any clinically            significant ECG abnormality at baseline (before dosing) will            be excluded.        -   Pulse oximetry will be continuously monitored over the same            time course.        -   12-lead ECG        -   A 12-lead ECG will be performed at screening and on Day 1            before dosing and at check-out. Corrected QT interval (QTc)            will be recorded.        -   Vital Signs        -   With the subject in a seated or semi-reclined position, BP,            HR, RR will be recorded at screening, predose (within 120            minutes before dosing), and within 5 minutes before the PK            blood draws at approximately 10, 20, 30, and 45 minutes and            1, 1.5, 2, 3, 4, 6, and 9 hours after dosing, as well as 2.5            hours after dosing (no PK draw). Pulse oximetry values will            be recorded from the continuous monitor at approximately the            same time points.        -   Level of Alertness and Sedation        -   Level of sedation will be assessed using the Modified            Observer's Assessment of Alertness/Sedation (MOAA/S) Score.            Chemik D A, Gillings D, Laine H, et al. Validity and            reliability of the Observer's Assessment of            Alertness/Sedation Scale: study with intravenous midazolam.            J Clin Psychopharmacol 1990 August; 10(4):244-51. Sedation            (MOAA/S score) will be recorded within 15 minutes before            dosing, at 15 minutes after dosing, at approximately            15-minute intervals until 3 hours after dosing, and at            approximately 30-minute intervals thereafter until            approximately 9 hours after dosing, provided that the            subject had a score of 5 on at least the 3 consecutive            MOAA/S scores immediately prior to the 3-hour timepoint.            Subjects who have not demonstrated 3 consecutive MOAA/S            scores of 5 immediately prior to the 3-hour timepoint will            continue with MOAA/S assessments at 15-minute intervals            until they demonstrate 3 consecutive MOAA/S scores of 5,            with MOAA/S scores recorded at 30-minute intervals            thereafter until approximately 9 hours after dosing. Cohen            LB. Clinical trial: a dose-response study of fospropofol            disodium for moderate sedation during colonoscopy. 2008;            Aliment Pharmacol Ther 27, 597-608. Subjects who do not have            a MOAA/S score of 5 at 9 hours after dosing will remain in            the clinic until they have reached a MOAA/S score of 5 and            are determined by the PI to be awake, alert, and safe to            leave (even if the time in the clinic extends beyond 9            hours).        -   Laboratory Assessments        -   In Part 1 of the study, Hematology, biochemistry, and            urinalysis will be assessed at screening and at check-out.        -   In Part 2 of the study, Hematology, biochemistry, and            urinalysis will be assessed at screening and at check-out at            each treatment visit.        -   Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIV            antigen and antibody detection will be performed at            screening. Alcohol breath test, urine cotinine test, and            urine drug screen will be performed at screening and at each            clinic check-in. For women, a urine pregnancy test will be            performed at screening, and a serum pregnancy test will be            performed before dosing (at each clinic check-in or in the            morning of Day −1).        -   Physical Examination        -   A complete physical examination will be performed at            screening. A brief physical examination will be performed at            check-in and at check-out.    -   Exploratory Evaluations At 2 hours (±15 minutes) after dosing,        the PI (or designate) will ask the subject several mental status        questions, such as the following: What is your name? Where are        you now? What month or season is it? The subject's answers will        not be recorded. However, based on the subject's responses, the        PI (or designate) will give a subjective assessment as to        whether 2 hours after dosing the subject would be able to        provide a reliable report of hypothetical migraine pain or other        symptoms. The assessment will be recorded in the following        categorical format:        -   Yes (In my judgment, if this subject had a migraine            headache, in his/her present condition he/she would be able            to provide a reliable report of his/her migraine pain or            other symptoms.)        -   No (In my judgment, if this subject had a migraine headache,            in his/her present condition he/she would not be able to            provide a reliable report of his/her migraine pain or other            symptoms.)        -   Uncertain (In my judgment, if this subject had a migraine            headache, in his/her present condition he/she it is not            clear whether this subject would be able to provide a            reliable report of migraine pain or other symptoms.)    -   Adverse Events AEs will be evaluated regarding seriousness,        severity, and relationship to study drug.        -   Some degree of sedation is an expected and potentially            therapeutic effect of the study drug. Therefore, sedation            rated by the PI as mild or moderate will be considered an            expected AE.    -   Check-out/Early Termination Procedures The following procedures        will be done at each clinic check-out or for early termination        (when applicable): hematology, blood chemistry, urinalysis,        brief physical examination, vital signs, pulse oximetry, 12-lead        ECG, oral temperature, AE monitoring.        -   Subjects will be instructed not to drive or operate heavy            machinery for 24 hours after dosing.    -   Analytical Method Fospropofol and propofol will be analyzed in        plasma samples using validated LC/MS/MS methods. Additional        plasma samples may be drawn and stored for possible future        bioanalysis of metabolites or other analytes.    -   Pharmacokinetic Parameters The following PK parameters will be        calculated for both fospropofol and propofol plasma        concentrations: AUC_(0-t), AUC_(0-inf), C_(max), residual area,        T_(max), t_(1/2 el), K_(el), Cl/F, Cl/F/kg, Vd/F, and Vd/F/kg.    -   Statistical Analyses A complete description of the statistical        analyses to be performed for the safety, tolerability, and PK        data will be presented in a Statistical Analysis Plan (SAP).        -   Safety and Tolerability        -   Safety and tolerability data will be reported using            descriptive statistics. Summary statistics for            treatment-emergent adverse events (TEAEs) will be reported            by dose. Changes from baseline values in vital signs, ECG,            and clinical laboratory parameters will be reported by dose.        -   PK        -   Interim bioanalysis and PK analyses for propofol are to be            performed after completion of Part 1. These results will be            used to inform the PK sampling schedule for Part 2.        -   Summary statistics will be used to describe the PK profile            of both fospropofol and propofol for the Fospropofol            Disodium 200 mg tablet (Part 1). Summary statistics will be            used to describe the PK profile of both fospropofol and            propofol for each of the three treatments in Part 2. Summary            statistics will include at minimum arithmetic and geometric            means for AUC_(0-t), AUC_(0-inf), AUC_(0-2h), and C_(max).            T_(max) will be characterized by median and range.        -   Pair-wise comparisons among the 3 treatments in Part 2 will            be undertaken using log-transformed data to calculate the            ratio of geometric means with 90% CI for PK parameters            including at minimum Cmax, AUC_(0-2h), AUC(0-T), and            AUC(0-inf). Tmax values will be compared using a            non-parametric (Wilcoxon) test. (Details to be provided in            the SAP.) All inferential statistical analyses will be            interpreted, in an exploratory sense only, at an alpha level            of 5% for statistical significance.

Example A19—Study A19

Safety-tolerability, Pharmacokinetics, and EEG Photoparoxysmal ResponseFollowing Single Doses of Fospropofol Disodium Administered toPhotosensitive Adult Subjects With Epilepsy

-   -   Study Drug Fospropofol Disodium    -   Study Phase and Type Phase 1b Single-center, double-blind,        placebo-controlled, randomized 4-sequence, 4-period,        4-treatment, single ascending-dose crossover trial    -   Objectives Primary Objectives        -   To describe the safety-tolerability of single oral ascending            doses of fospropofol disodium administered orally at 3 dose            levels compared with placebo in adult photosensitive            subjects with epilepsy        -   To describe the pharmacokinetics (PK) of fospropofol and            propofol after single ascending doses of fospropofol            disodium administered orally at 3 dose levels in adult            photosensitive subjects with epilepsy        -   Secondary Objectives        -   To evaluate single ascending oral doses of fospropofol            disodium at 3 dose levels compared with placebo regarding            effects on the EEG epileptiform photoparoxysmal response            induced by intermittent photic stimulation (IPS) as a            measure of potential antiepileptic activity.        -   To explore the effect of fospropofol disodium on PK of            concomitant antiseizure medications (ASMs) as an aid to            interpreting safety-tolerability of fospropofol disodium.    -   Study Design This is a Phase 1b, double-blind,        placebo-controlled, randomized 4-sequence, 4-period,        4-treatment, single ascending-dose crossover trial in subjects        with epilepsy who have a known stable IPS-induced        photoparoxysmal response on EEG. Potential subjects will be        screened to ensure they have a stable photosensitivity range.        After screening, subjects who enter the study will return for 4        treatment visits (Visits 1, 2, 3, and 4), each lasting        approximately 1 day (no overnight stays). At each visit,        subjects will receive 1 dose of fospropofol disodium at one of 3        dose levels (200 mg, 400 mg, or 800 mg) or 1 dose of placebo.        -   Treatment visits will be separated by a minimum washout            period of 7 days (maximum 4 weeks). Thus, the duration of            subject participation is expected to range from            approximately 4 weeks to a maximum of approximately 16            weeks.        -   Subjects will be randomly allocated to 1 of 4 treatment            sequences (in blocks of 4 subjects) comprising the 3            ascending fospropofol disodium dose levels interspersed with            a placebo treatment at Visit 1, 2, 3, or 4 (see            Randomization below). Patients and examining physicians will            be blinded to the position of the placebo visit in the            sequence.        -   To assess the photosensitivity range of the photoparoxysmal            response, subjects will be exposed to IPS—i.e., flickering            diffuse white light—at a range of frequencies. The            individual's photosensitivity range will be determined as            the difference between the highest and lowest flash rates            that consistently elicit a generalized photoparoxysmal EEG            response.        -   At each treatment visit, the photosensitivity range will be            assessed before dosing and at 15 and 30 minutes, and 1, 2,            3, 4, and 6 hours after dosing. For each of the 3 dose            levels, the photosensitivity range after treatment with            active drug will be compared with the photosensitivity range            after placebo administration. During each of the 4 treatment            visits (4 in-clinic treatment days), blood samples will be            drawn to characterize the PK of fospropofol disodium and            propofol, assess levels of ASMs, and to assess laboratory            safety parameters.        -   Depending on responses, additional postdose time points for            IPS assessments may be added during Treatment Visit 1, 2, 3,            or 4. Subjects may be brought back for 1 or 2 additional            visits to evaluate an intermediate fospropofol disodium dose            level, to revisit a particular dose, or to evaluate            different PK time points. In such cases, the fospropofol            disodium dose at any one session will not exceed 800 mg, and            the total dose given to an individual subject over the            course of the entire study will not exceed 2000 mg, which            was the highest single dose administered in the Sponsor's            previous Phase 1a study in healthy volunteers (Study A16)    -   Justification for Dose Selection of the doses for this study is        based on the results of the Sponsor's prior Phase 1a study in        healthy volunteers (Study A16). The highest dose in the present        study, 800 mg, was well-tolerated in Study A16. The 800-mg dose        was also selected as the dose to be used in the ongoing Phase 1b        single-dose study in subjects with migraine. In the present        study, subjects will receive single doses of 200, 400, and 800        mg fospropofol disodium on separate occasions separated by at        least 7 days of washout between doses. Based on PK results from        Study A16, accumulation of either fospropofol or its propofol        metabolite is not expected. In any case, as noted above, the        total dose received by an individual subject completing all        treatments in the current study will not exceed 2000 mg.    -   Subject Selection Approximately 4 to 8 subjects will be enrolled        in an effort to end the study with a minimum of 4 subjects        completing all 4 treatment periods (i.e., 4 subjects with        evaluable data for placebo and all of the 3 fospropofol disodium        dose levels).    -   Inclusion Criteria Subjects must meet all of the following        criteria at screening to be enrolled in the study:        -   1. Written informed consent approved by the Institutional            Review Board (IRB) given before any study-related procedures            are performed        -   2. Male or female, ≥18 and ≤60 years of age at the time of            signed informed consent        -   3. Body mass index (BMI) 18.0 and ≤40.0 kg/m² and body            weight ≥50.0 kg for men and ≥45.0 kg for women. Subjects            with BMI up to 45 kg/m² may be considered at the discretion            of the Investigator with agreement of the Sponsor.        -   4. A diagnosis of epilepsy for which subjects have been            treated on a stable regimen of 0-3 concomitant ASMs for at            least 30 days before screening.        -   5. A diagnosis and history of photoparoxysmal response on            EEG (confirmed by prescreening, if necessary).        -   6. At least 3 EEGs performed during the screening visit must            have a reproducible IPS-induced photoparoxysmal response on            EEG of ≥3 points on a frequency assessment scale in at least            1 eye condition (eyes closing, eyes closed, or eyes open).        -   7. Subjects in otherwise good health (with the exception of            epilepsy), as determined by the Investigator via the medical            history, a physical examination, and screening laboratory            investigations.        -   8. Female subjects must fulfill at least one of the            following:        -   f) Surgically sterile, defined as women who have had a tubal            ligation, hysterectomy, or bilateral oophorectomy at least 6            months prior to screening.        -   g) Post-menopausal, defined as absence of menses for at            least 12 months prior to screening.        -   h) Women who are sexually active and at risk for pregnancy            must agree to avoid pregnancy and use a medically acceptable            method of contraception from at least 30 days prior to            screening until 30 days after study drug administration.            -   Medically acceptable methods of contraception include                hormonal contraception, hormonal or non-hormonal                intrauterine device, double barrier method (simultaneous                use of male condom with intravaginally applied                spermicide and diaphragm or cervical cap), or male                partner vasectomy at least 6 months previously. Complete                abstinence alone can be used as a method of                contraception.        -   9. Male subjects who are not vasectomized for at least 6            months and who are sexually active with a non-sterile female            partner (see definitions of surgically sterile and            post-menopausal above) must agree to use one of the            following acceptable contraceptive methods throughout the            study and for 90 days after the study drug administration            Complete abstinence alone can be used as a method of            contraception.        -   i) Simultaneous use of male condom and, for the female            partner, intrauterine contraceptive device with or without            hormone release (placed at least 4 weeks previously)        -   j) Simultaneous use of male condom and, for the female            partner, hormonal contraception        -   k) Simultaneous use of male condom and, for the female            partner, intravaginally applied spermicide with diaphragm or            cervical cap        -   10. As assessed by the Investigator, able to comprehend the            nature of the study, capable of giving written informed            consent/assent to participate in the study in accordance            with ICH Good Clinical Practice (GCP) guidelines, and able            to communicate effectively with clinic staff        -   11. Agrees to refrain from strenuous exercise the day before            screening and during the day prior to each treatment day    -   Exclusion Criteria Subjects are not eligible for this study if        one or more of the following conditions exist:        -   1. History of non-epileptic seizures (e.g., metabolic,            structural, or pseudo-seizures).        -   2. Female subjects who are pregnant (positive serum            pregnancy test at screening) or lactating.        -   3. Individuals of reproductive potential who do not agree to            use effective birth control methods (as defined in the            inclusion criteria above).        -   4. An active central nervous system (CNS) infection,            demyelinating disease, degenerative neurological disease, or            any CNS disease deemed to be progressive during the course            of the study that may confound the interpretation of the            study results.        -   5. Clinically significant active liver disease, porphyria or            with a family history of severe hepatic dysfunction            indicated by abnormal liver function tests greater than 3            times the upper limit of normal (AST and ALT).        -   6. Positive serologic test for hepatitis B, hepatitis C, or            HIV at screening. (Reflex HCV RNA testing will be performed            for any positive hepatitis C screening test. If the results            of reflex testing are negative, the subject may be deemed            eligible for the study.)        -   7. Any clinically significant laboratory abnormality that in            the opinion of the Investigator would exclude the subject            from the study. Laboratory tests may be repeated at the            Investigator's discretion.        -   8. Any clinically significant psychiatric illness or            psychological or behavioral problems that in the opinion of            the Investigator would interfere with the subject's ability            to participate in the study.        -   9. History of any of the following:        -   l) Significant alcohol abuse within 1 year prior to            screening or regular use of alcohol within 6 months prior to            screening (more than 14 units of alcohol per week [1            unit=150 mL of wine, 360 mL of beer, or 45 mL of 40%            alcohol]), or        -   m) Significant drug abuse or use of cocaine, phencyclidine            [PCP], crack, opioid derivatives including heroin, or            amphetamine derivatives, or similar drugs within 1 year            prior to screening. Use of marijuana or tetrahydrocannabinol            |THC|-containing products is permitted unless in the            Investigator's opinion such use would impact the safety of            the subject or interpretation of the study results. If            marijuana is used, use must be consistent throughout the            study.        -   10. Any of the following at screening:        -   n) A positive alcohol breath test or        -   o) A positive urine drug screen, unless consistent with an            ongoing prescription drug as documented by the Investigator.            Detectable levels of marijuana (THC or metabolites) in the            urine drug screen are not exclusionary if in the            Investigator's documented opinion the positive test does not            signal a clinical condition that would impact the safety of            the subject or interpretation of the study results.        -   11. Diagnosis of sleep apnea.        -   12. Subjects who have participated in any other trials            involving an investigational product or device within 30            days before screening.        -   13. Subjects receiving more than 3 concomitant ASMs for            epilepsy.        -   14. Subjects who have intolerance to and/or difficulty with            blood sampling through venipuncture.        -   15. Employees or immediate families (defined as spouse,            significant-other, parent, child, or sibling, whether            adopted or biologic) of an employee of Epalex Corporation,            its affiliates, or partners; Investigator or study center            personnel directly affiliated with this study and/or their            immediate families.        -   16. Score of >0 on the Sheehan Suicidality Tracking Scale            (S-STS) for a recall period of 30 days prior to screening.    -   Study Drug and Dosage Form Fospropofol disodium is formulated        for oral administration in an appropriate number of        powder-filled hydroxypropyl methylcellulose (HPMC) capsules.        Each HPMC capsule contains 200 mg of fospropofol disodium        (uncorrected for sodium content) and no inactive ingredients.    -   Dose Levels Each subject will receive 3 ascending oral doses of        fospropofol disodium (200 mg, 400 mg, and 800 mg) on 3 different        days, interspersed according to a randomization scheme with 1        day on which they will receive placebo (see Randomization).    -   Administration of Study Drug Subjects will receive 1 dose of        study drug at approximately 8:30 to 9:00 am on each treatment        day.        -   Each dose (4 capsules) will be administered with water at            ambient temperature in the amount of approximately 240 mL (8            oz). The amount of water may be increased to approximately            355 mL (12 oz) if needed.    -   Randomization Subjects will be randomly allocated in blocks of 4        subjects to 1 of 4 treatment sequences (A, B, C, or D) according        to the scheme shown below:

Treatment Visits Sequence Visit 1 Visit 2 Visit 3 Visit 4 A PlaceboFOSPRO- FOSPRO- FOSPRO- POFOL POFOL POFOL DISODIUM DISODIUM DISODIUM 200mg 400 mg 800 mg B FOSPRO- Placebo FOSPRO- FOSPRO- POFOL POFOL POFOLDISODIUM DISODIUM DISODIUM 200 mg 400 mg 800 mg C FOSPRO- FOSPRO-Placebo FOSPRO- POFOL POFOL POFOL DISODIUM DISODIUM DISODIUM 200 mg 400mg 800 mg D FOSPRO- FOSPRO- FOSPRO- Placebo POFOL POFOL POFOL DISODIUMDISODIUM DISODIUM 200 mg 400 mg 800 mg

-   -   Screening Procedures Prescreening        -   Most potential subjects will have known photosensitivity            based on previous evaluation of their photoparoxysmal            response on EEG via IPS. If a potential subject has not had            an EEG showing a photoparoxysmal response within the past            year, or if their ASMs have been adjusted since the last            EEG, the subject may be asked to come to the clinic for a            1-hour prescreening EEG with IPS to determine preliminary            eligibility for the trial. In this case, the subject would            be asked to give written informed consent for the            prescreening assessments. If the subject has a reproducible            IPS-induced photoparoxysmal response on EEG of ≥3 points            they will be scheduled to return for the screening visit.        -   Screening Visit        -   The screening visit is to occur within 30 days prior to the            first dosing visit and consists of obtaining informed            consent, confirming that the subject meets all inclusion and            exclusion criteria, and collecting baseline assessments.        -   Screening Procedures        -   Screening procedures will comprise written informed consent            and review of inclusion/exclusion criteria, including            demographic data; medical history; medication history; full            neurological and physical examination; body measurements            (height, weight, BMI); 12-lead ECG; laboratory assessments            (hematology, blood chemistry, HIV, hepatitis B and C            serology, serum pregnancy test for women of childbearing            potential; ASM levels; urinalysis, urine drug screen;            alcohol breath test); the Sheehan Suicidality Tracking            Scale; pulse oximetry and vital signs (BP, HR, RR,            temperature).        -   Medication history will be obtained by interview and will            include drug allergies and history of epilepsy-related            medications during the month prior to screening.        -   Baseline IPS Assessment and Determination of Most Sensitive            Eye Condition        -   At the screening IPS assessment, all eye conditions will be            assessed (eyes closing, eyes closed, or eyes open). The EEG            is to be read by The Epilepsy Study Consortium, and the            results must be available before the subject can return for            the first treatment visit. At least 3 of the EEGs performed            during the screening visit must demonstrate an IPS-induced            photoparoxysmal response on EEG, defined as a change of 23            points on a frequency assessment scale in at least 1 eye            condition. The most sensitive eye condition will be            determined after the screening visit by averaging the range            over all of the time points.    -   Treatment Visits (1, 2, 3, and 4) The subject should present to        the epilepsy center for treatment visits at approximately 7 am,        in time for predosing procedures to be completed so that dosing        can occur at approximately 8:30 to 9 am. The following        procedures should be performed before dosing (see Schedule of        Events):        -   Urine pregnancy test for all female subjects of childbearing            potential. Drug and alcohol screen.        -   Sheehan-STS.        -   Confirm that inclusion/exclusion and study restriction            criteria are met.        -   Place EEG leads for IPS testing of the of the EEG            epileptiform photoparoxysmal response.        -   Start continuous monitoring of pulse oximetry at least 15            minutes before the IPS assessment; record SpO₂ values from            the continuous monitor within 15 minutes before the IPS            assessment.        -   Assess vital signs within 15 minutes before the IPS            assessment.        -   Assess baseline sedation level with a visual analog scale            within 15 minutes before the IPS assessment.        -   Conduct predose IPS session in the most sensitive eye            condition (determined at screening).        -   Collect blood samples for predose EP103/propofol and ASM            levels. Postdose assessments should be performed in the            following order (see Table 1):        -   SpO₂ values recorded from the continuous monitor.        -   Vital signs.        -   Sedation assessed with the VAS-S.        -   IPS sessions in the most sensitive eye condition.        -   Blood samples for PK of EP103 and ASM levels.        -   AEs.    -   IPS Assessments IPS assessments will be performed at        prescreening (if applicable), at screening, and at each        treatment visit. At treatment visits, IPS sessions will be        performed in the most sensitive eye condition, as determined at        screening.        -   Prescreening, screening, and predose IPS assessments will            begin at approximately 8:00 to 8:30 am. Postdose IPS            assessments will begin at 15 and 30 minutes and at 1, 2, 3,            4, and 6 hours after dosing (f 5 minutes).        -   Prescreening and Screening        -   The EEG is to be read by The Epilepsy Study Consortium, and            the results must be available before the subject can return            for the first treatment visit. At least 3 of the EEGs            performed during the screening visit must demonstrate an            IPS-induced photoparoxysmal response on EEG, defined as a            change of ≥3 points on a frequency assessment scale in at            least 1 eye condition. The most sensitive eye condition will            be determined after the screening visit by averaging the            range over all of the time points.        -   Postdose        -   IPS sessions will be repeated in the most sensitive eye            condition at 15, and 30 minutes and 1, 2, 3, 4, and 6 hours            after dosing.    -   PK Sampling Blood samples will be collected at each treatment        visit for analysis of fospropofol and propofol PK, and separate        samples will be drawn for assay of concomitant ASM levels.        -   Blood samples for fospropofol disodium/propofol PK and ASM            levels will be drawn immediately after the end of the            predose IPS session (within 30 minutes before dosing), at 10            minutes after dosing, and immediately after the end of each            postdose IPS session (within 10 minutes after the start of            the IPS measurement), with the exception that there will be            no PK blood draw at 3 hours postdose. In case of a serious            adverse event (SAE) or early withdrawal, if possible, a PK            blood draw should be collected at or near the time the            subject reports the SAE or at the time of withdrawal.        -   Sample collections done outside the predefined time windows            will not be considered as protocol deviations, since actual            postdose sampling times will be used for PK and statistical            analyses.        -   The time points of the PK sample collection may be changed,            or an additional postdose time point may be added during            Treatment Visit 1, 2, 3, or 4 or an additional visit.            However, the total number of PK time points (including            predose) will not exceed 9 per visit.    -   Total Blood Volume Drawn The total amount of blood collected        from each subject over the course of this study will not exceed        540 mL and will not exceed 10.5 mL/kg over an 8-week period. In        subjects of low body weight, the period between study visits may        be extended (to up to 4 weeks) to meet this criterion.    -   Adverse Events Subjects will be instructed to inform clinical        personnel of any potential AEs, i.e., untoward medical symptoms        and/or events that may arise from arrival at the clinic for        check-in until clinic discharge.        -   Some degree of sedation is an expected and potentially            therapeutic effect of the study drug. Although sedation,            including events described as feeling “drowsy,” “sleepy,”            “relaxed,” etc., will be expected, such terms if expressed            by the subject will be recorded as AEs, and severity will be            rated by the site Investigator as mild, moderate, or severe.            Because subjects will be allowed to sleep after dosing if            desired, sleep itself will not be considered an AE.    -   Stopping Rules The study will be stopped if any 2 subjects        experience the same type of worsening (1, 2, or 3 below), or a        total of 3 subjects demonstrate any of the following 3 criteria        for worsening:        -   If a subject has a widening of the photosensitivity range by            more than 3 points on 2 consecutive occasions after dosing            as compared to the screening day, the photic stimulation            will be terminated, and the subject will be unable to            participate in further testing that day.        -   If a subject experiences a generalized tonic-clonic seizure            during any study day, and they have not had a generalized            tonic-clonic seizure in the 6 months prior to enrollment,            the study will be terminated for that subject. If any            subject experiences a generalized tonic-clonic seizure            during photic stimulation, the study will be terminated for            that subject, and they will not be permitted to participate            in further testing.        -   If in the opinion of the Investigator a subject has evidence            of proconvulsive activity on the EEG after administration of            the study medication, (e.g. increase in spike-wave activity)            then the study will be terminated for that subject and they            will not be permitted to participate in further testing that            day.        -   If in the opinion of the Investigator or the Sponsor a            subject has evidence of excessive sedation manifest by            clinically significant changes in pulse oximetry or changes            in vital signs after administration of the study medication,            the subject may be permitted to participate in further            testing on that day at the discretion of the Investigator.            If excessive sedation occurs in any period other than the            fourth period, the subject will not proceed to the next            period. In such cases, an open-label placebo session (with            the subject and the EEG reader blinded) may be substituted            for the next planned blinded treatment to ensure that the            subject completes the study with at least one IPS under            placebo treatment. Any such case will be fully documented in            the report and identified in the data analysis.    -   Analytical Method Fospropofol and propofol concentrations will        be analyzed in plasma samples using a validated method.    -   Statistical Considerations A complete description of the        statistical analyses to be performed for the safety,        tolerability, and PK data will be presented in a Statistical        Analysis Plan (SAP).        -   Safety and Tolerability        -   Safety and tolerability data will be reported using            descriptive statistics. Summary statistics for TEAEs will be            reported. Changes from baseline values in vital signs, ECG,            and clinical laboratory parameters will be reported.        -   PK        -   Summary statistics will be used to describe the PK profile            of both fospropofol and propofol. Summary statistics will            include at minimum arithmetic and geometric means for            AUC_(0-t), AUC_(0-inf), and C_(max). T_(max) will be            characterized by median and range. Exploratory analyses may            be performed in an effort to characterize the influence of            covariates on PK.        -   The observed concentrations of concomitant ASMs will be            listed and presented as summary statistics. Pharmacokinetic            parameters for concomitant ASMs may be calculated, listed,            and presented as summary statistics if feasible.        -   Exploratory analyses may be performed in an effort to            characterize the effect, if any, of fospropofol disodium on            concentrations of concomitant ASMs. Such analyses could            provide useful information as to the potential for drug-drug            interactions requiring further evaluation in the subsequent            development of fospropofol disodium in the treatment and            prevention of epileptic seizures.        -   Analyses of Photoparoxysmal Response        -   Descriptive statistics will be presented including the means            and standard deviations of photosensitivity range for each            subject, for each day. Graphical displays of the data for            each subject will allow exploration of inter- and            intra-subject variability.

Study Assessments

Intermittent Photic Stimulation Assessments

IPS assessments will be performed at prescreening if applicable, atscreening, and at each treatment visit. At treatment visits, IPSsessions v ill be performed in the most sensitive eye condition, asdetermined at screening.

Prescreening (if applicable), screening, and predose IPS assessmentswill begin at approximately 8:00 to 8:30 am. Postdose IPS assessmentswill begin at 15 and 30 minutes and at 1, 2, 3, 4, and 6 hours afterdosing (±5 minutes).

All IPS assessments for screening and during the study will be performedusing the systematic protocol designed by Dorothee Kasteleijn.Kasteleijn-Nolst Trenite D G, Marescaux C, Stodieck S, Edelbroek P M,Oosting J. Photosensitive epilepsy: a model to study the effects ofantiepileptic drugs. Evaluation of the piracetam analogue,levetiracetam. Epilepsy Res 1996; 25:225-230. The procedure will be asfollows:

Photic Stimulator

The IPS will be carried out using the photic stimulator, Grass PS 33,with an un-patterned glass lamp and an intensity of 100 cd/m2/flash.

EEG Measurement with Video Monitoring

IPS session will be recorded with standard 19-21-channel EEG equipmentincluding video monitoring and precise recording of duration andfrequency of the flashes (sensor or connection with the photicstimulator).

Electrode Placement:

The international 10-20 system with 2 additional channels, one foreye-movements (to detect changes in eye condition more easily) and onefor flash frequencies.

Montage:

A 19-21-channel recording system will be used with a bipolar derivationwith emphasis on the parieto-temporal-occipital area (maximum andspreading of EA): The display montage will include T4-T6-O2-O1-T5-T3 andT4-P4-Pz-P3-T3, apart from 2×4 (8) frontal to occipital leads.

Settings:

-   -   Amplification: 7-10 microV/mm    -   High Frequency Filter: 35-70 Hz    -   Time constant: 0.3-0.6 sec    -   Display speed: 30 mm/sec

Methods:

The lighting will be dimmed but never completely darkened so as topermit observation of the subject, to control ocular fixation, and tonote possible clinical ictal phenomena. Subjects will be seated with thephotic stimulator at 30-cm distance from the nasion and will be asked tofixate on the center of the lamp.

Throughout the study the flash frequency will be recorded. The eyecondition per stimulus for assessment purposes will also be recorded.

In order to enable discrimination between spontaneous and IPS-evokeddischarges, at the beginning of the trial day the subject will beassessed for ≥2.5 minutes with eyes open and another 2.5 minutes witheyes closed without any stimulation.

Trains of flashes at constant frequency will be delivered for as closeto 4 seconds as possible, and no more than 5 seconds, except when aphotoparoxysmal response is elicited, when photic stimulation will beimmediately stopped. Intervals between successive flash trains at agiven frequency will last for at ≥5 seconds. Determination of thephotosensitivity ranges will be assessed with separate trains of flashesof 4-5 seconds duration (or less if generalized epileptic activityoccurs).

Flashes will be administered at standard frequencies of 2, 5, 8, 10, 13,15, 18, 20, 23, 25, 30, 40, 50 and 60 Hz.

At the screening visit, each frequency will be assessed in 3 eyeconditions (eyes closing, eyes closed, eyes open), commencing at 2 Hz.As soon as generalized EEG epileptiform activity appears, thestimulation for that particular frequency in a particular eye conditionwill be instantly terminated. For the other eye conditions, ascendingfrequencies will be used until generalized epileptiform activity isseen. This will determine the lower threshold frequencies for each eyecondition.

Similar assessments will then be carried out starting at 60 Hz anddescending through the standard frequencies. Again, the stimulator willbe turned off immediately if a generalized response is seen to avoidoccurrence of a seizure, and the sequence will be stopped at that pointin that specific eye condition. For each eye condition, the upperthreshold frequencies are thus determined.

The combination of lower and upper frequencies gives a total of 3photosensitivity ranges, one per eye condition. If there is any doubt ofthe interpretation during any of the assessments (for example, blinkingduring the eyes open condition provoking epileptiform activity), thestimulation in the same eye condition will not be repeated. Photicstimulation will not be carried out between the upper and lowerthresholds in order to minimize the risk of inducing a seizure. Thismethod has been found to be the safest, as it prevents elicitation ofseizures by avoiding stimulation of the subject at their most sensitivefrequencies. The range for each subject will be recorded in the CRF.

Interpretation of Results:

The EEG technician performing the testing will remain blinded throughoutthe study.

The procedure for determining photosensitivity thresholds described hereis interactive and requires immediate decisions by the Investigatorduring each assessment. The tracings will also be analyzedretrospectively to confirm that the limiting frequencies were thethreshold for eliciting a response as defined above.

Blood Sample Collection and Processing

Blood samples will be collected and processed. The total volume of blooddrawn from each subject over the course of this study will not exceed540 mL and will not exceed 10.5 mL/kg over an 8-week period. In subjectsof low body weight, the period between study visits may be extended (toup to 4 weeks) to meet this criterion. The maximum total amount of blooddrawn includes standard screening and postdose clinical laboratorytests, pharmacokinetic analysis (fospropofol and propofolconcentrations), ASM concentrations, and any additional treatment visitsfor evaluation of intermediate doses, revisiting a particular dose, orevaluation of different PK time points.

Sampling for Fospropofol/Propofol PK and ASM Assessment

Blood samples will be collected at each treatment visit for analysis offospropofol and propofol PK, and separate samples will be drawn forassay of concomitant ASM levels.

Blood samples for fospropofol disodium/propofol PK and ASM levels willbe drawn immediately after the end of the predose IPS session (within 30minutes before dosing), at 10 minutes after dosing, and immediatelyafter the end of each postdose IPS session (within 10 minutes after thestart of the IPS measurement), with the exception that there will be noPK blood draw at 3 hours postdose. In case of an SAE or earlywithdrawal, a PK blood draw should be collected, if possible, at or nearthe time the subject reports the SAE or at the time of withdrawal.

Sample collections done outside the predefined time windows will not beconsidered as protocol deviations, since actual postdose sampling timeswill be used for PK and statistical analyses.

The time points of the PK sample collection may be changed, or anadditional postdose time point may be added during Treatment Visit 1, 2,3, or 4 or an additional visit. However, the total number of PK timepoints (including predose) will not exceed 9 per visit.

When appropriate, an indwelling i.v. catheter will be used for bloodcollection to avoid multiple skin punctures. Otherwise, blood sampleswill be collected by direct venipuncture.

In case of an SAE or early withdrawal, if possible, a PK blood drawshould be performed at or near the time the subject reports the SAE orat the time of withdrawal from the study.

Safety Laboratory Assessments

Hematology samples will be drawn at screening and clinic check-out ateach treatment visit. Hematology will include complete blood count withdifferential, hemoglobin, and hematocrit.

Serum chemistry samples will be drawn at screening and clinic check-outat each treatment visit. Serum chemistry assessments will includealbumin, alanine aminotransferase, alkaline phosphatase, aspartateaminotransferase, calcium, chloride, carbon dioxide/bicarbonate,creatinine, glucose, phosphate, potassium, sodium, total bilirubin,total protein, and blood urea nitrogen (BUN).

Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIV antigen andantibody detection will be performed at screening. (Reflex HCV RNAtesting will be performed for any positive hepatitis C screening test.If the results of reflex testing are negative, the subject may be deemedeligible for the study.)

Urine for urinalysis will be collected at screening and clinic check-outat each treatment visit. Urinalysis will include macroscopicexamination, pH, specific gravity, protein, glucose, ketones, bilirubin,occult blood, nitrite, urobilinogen, and leukocytes. Unless otherwisespecified, microscopic examination will be performed on abnormalfindings according to standard procedure.

For women, a serum pregnancy test will be performed at screening, and aurine pregnancy test will be performed at clinic check-in at eachtreatment visit.

A urine drug screen (amphetamines, methamphetamines, barbiturates,benzodiazepines, THC, cocaine, opiates, PCP,3,4-methylenedioxy-methamphetamine (MDMA), methadone) and an alcoholbreath test will be performed at screening and at clinic check-in ateach treatment visit.

Other Safety Procedures and Assessments

Medical Surveillance and AE Monitoring

The Investigator is to be on site from approximately 30 minutes prior toeach dosing until clinic discharge.

The study site is to be staffed to assess and manage potential risksthat may occur with sedative-hypnotic agents. Subjects are to becontinuously monitored for oxygen desaturation using a pulse oximeterwith an alarm, and supplemental oxygen should be available. In addition,although these conditions are unlikely to occur at the selected dose offospropofol disodium, subjects should be monitored for early signs ofhypotension, apnea, or airway obstruction from approximately 30 minutesprior to dosing of study drug until clinic discharge. This role may befulfilled by the Investigator or designee trained in airway management.

Safety parameters, including laboratory results, will be evaluated bythe Investigator in the context of clinical trial safety. Any abnormalmeasurement is to be repeated if judged necessary by the Investigator.Further action to ensure subject safety may be taken at theInvestigator's discretion.

Physical Examination

A complete physical and neurological examination will be performed atscreening, and abbreviated physical and neurological examinations willbe performed at clinic check-out at each treatment visit and at earlytermination, if applicable.

The complete physical examination at the screening visit will assess anyphysical abnormalities and will include at a minimum, assessments of thefollowing body systems: general appearance, overall status of the head,ears, eyes, nose, throat (HEENT), neck, abdomen, lymph nodes, skin,cardiovascular/heart, pulmonary, musculoskeletal, and neurological(level of alertness [more detailed mental status not required unlessindicated], speech, cranial nerves, motor strength and tone, cerebellar,sensory, deep tendon reflexes, and gait). Investigators should payspecial attention to clinical signs related to previous seriousillnesses.

Height and weight will also be measured and recorded at the screeningvisit.

The abbreviated physical examinations will assess general appearance,HEENT, cardiovascular, pulmonary, and neurological status. Theneurological examinations are to consist of level of alertness andspeech. Abbreviated physical examinations may be limited to recordingchange/no change from prior examinations, plus focused examination bysystem as directed by any AEs reported by the subject (where applicable)or any spontaneous symptom/complaint reported by the subject at the timeof the examination.

Sheehan Suicidality Tracking Scale

The Sheehan Suicidality Tracking Scale (S-STS) is a prospectivesuicidality rating scale to be completed by the Investigator or his/herdesignate. The scale includes 16 questions that allow a longitudinalevaluation of treatment-emergent suicidal ideation andtreatment-emergent suicidal behaviors.[25,26] Sheehan D V, Alphs L D,Mao L, et al. Comparative Validation of the S-STS, the ISST-Plus, andthe C-SSRS for Assessing the Suicidal Thinking and Behavior FDA 2012Suicidality Categories. Innov Clin Neurosci 2014; 11:32-46. Sheehan D V,Giddens J M, Sheehan I S. Status Update on the Sheehan-SuicidalityTracking Scale (S-STS) 2014. Innov Clin Neurosci 2014; 11:93-140.

The S-STS will be completed on a paper form at the site and will beadministered at the screening visit, at clinic check-in, and at cliniccheck-out (discharge) for each treatment visit. The recall period at thescreening administration will encompass the time period beginning 30days prior to the screening visit; the recall period at each treatmentvisit will be the time period since the previous visit. The total scoreplus the subject's response to each item will be recorded.

At screening, any subject with a response greater than zero to anyquestion must be excluded. At clinic check-in, any subject with aresponse greater than zero to any question other than Question 2 must bediscontinued from the study and the event recorded as an AE, nottreatment-emergent. Subjects with a response of 1 (“a little”) toQuestion 2 will be discontinued at the discretion of the Investigator.Subjects with a response greater than 1 on Question 2 will bediscontinued.

For each administration of the S-STS, the Investigator will immediatelyevaluate a subject with any response greater than zero to determine ifthat subject is at risk of self-harm or suicide. If this is the case,the Investigator must take appropriate measures to ensure the subject'ssafety and arrange for an appropriate mental health evaluation.

A 12-lead ECG will be performed at screening and at clinic check-out onTreatment Day 4 (or at early termination or check-out of an additionalvisit, if applicable). Corrected QT interval (QTc) will be recorded.

Pulse oximetry will be recorded at screening and continuously monitoredat each treatment visit from at least 15 minutes prior to the predoseIPS assessment until discharge from the clinic. The pulse oximeter is tohave an alarm set to give both audible and visual notifications whenSpO₂ drops to 90% or below. If the alarm signals, the subject should bearoused. Nasal oxygen should be considered if SpO₂ remains at 90% orlower after stimulation.

At each treatment visit, SpO₂ values will be recorded from thecontinuous monitor within 15 minutes before the predose IPS assessment,postdose within 10 minutes before each IPS assessment, between IPSassessments at 30-minute intervals (f10 minutes) until 6 hours afterdosing, and at clinic check-out.

Vital signs (BP, HR, RR, and temperature) are to be assessed atscreening and at each treatment visit within 15 minutes before thepredose IPS assessment, postdose within 10 minutes before each IPSassessment, between IPS assessments at 30-minute intervals (±10 minutes)until 6 hours after dosing, and at clinic check-out. The subject shouldbe in a seated or semi-reclined position for at least 5 minutes beforevital sign assessments. Vital sign assessments may be repeated at thediscretion of the Investigator.

Level of sedation will be assessed using a visual analog scale forsedation at screening, and at each treatment visit within 15 minutesbefore the predose IPS assessment, postdose within 10 minutes beforeeach IPS assessment, and at clinic check-out. If degree of sedation is aconcern, the duration of confinement may be extended, and safetymonitoring may continue at the discretion of the Investigator.

The visual analog scale (VAS) for sedation is a distinct 100-millimeterline anchored on the left end at full degree of impairment and on theright end at no degree of impairment, where indication of the degree ofimpairment perceived at the time of assessment is captured by markingthe appropriate position on the line between the anchor points. Themeasured distance of the mark from the left anchor will be recorded inmillimeters

Sedation will be measured using a 100-mm linear visual analog scale(VAS). The subject will be given 2 scales, 1 anchored by “Sedated” and“Alert, the other by “Sleepy and “Awake” and asked to “Place a verticalmark on the line indicating your feelings RIGHT NOW”. The location ofthe mark will be measured at a later time and the results will berecorded in mm from the left on the appropriate CRF.

An example of the subject VAS is provided below. The paper scales willbe provided to the site, and only originals can be used for subjectassessment. Photocopies cannot be provided for subject assessment.

Visual Analog Scale (VAS) for Sedation Assessment

Visual Analog Scale (VAS) for Sedation Assessment Sedated                       Alert Sleepy                        AwakeInstructions:Place a vertical mark on the line indicating your feelings RIGHT NOW.

Analytical Methodology

Samples will be transported to the bioanalytical facility packed onsufficient dry ice to keep them frozen for at least 72 hours.

Safety laboratory values and ASM concentrations will be analyzed usingvalidated methods. Fospropofol and propofol concentrations will beanalyzed in plasma samples using a validated method and in accordancewith the current regulations and guidelines in place for industry,including guidances on Bioanalytical Method Validation, Good LaboratoryPractice (GLP) for Nonclinical Laboratory Studies, and GCP ICH E6(R2).US Food and Drug Administration. Bioanalytical Method Validation:Guidance for Industry. 2018. Available athttps://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf.US 21 CFR Part 58. Good Laboratory Practice for Nonclinical LaboratoryStudies. Available athttps://www.ecfr.gov/cgi-bin/text-idx?SID=3be49f31878d0efa85f39ed3b84fcbe1&mc=true&node=se21.1.58_11&rgn=div8.US Food and Drug Administration. E6(R2) Good Clinical Practice:IntegratedAddendum to ICH E6(R1) Guidance for Industry. 2018. Availableat https://www.fda.gov/media/93884/download.

Statistical Considerations

A complete description of the statistical analyses to be performed forthe safety, tolerability, PK, and photoparoxysmal response data will bepresented in a Statistical Analysis Plan (SAP).

Safety and Tolerability

Safety and tolerability data will be reported using descriptivestatistics. Summary statistics for TEAEs will be reported. Changes frombaseline values in vital signs, ECG, and clinical laboratory parameterswill be reported.

PK

Summary statistics will be used to describe the PK profile of bothfospropofol and propofol. Summary statistics will include at minimumarithmetic and geometric means for AUC0-t, AUC0-inf, and Cmax. Tmax willbe characterized by median and range. Exploratory analyses may beperformed in an effort to characterize the influence of covariates onPK.

The observed concentrations of concomitant ASMs will be listed andpresented as summary statistics. Pharmacokinetic parameters forconcomitant ASMs may be calculated, listed, and presented as summarystatistics if feasible.

Exploratory analyses may be performed in an effort to characterize theeffect, if any, of fospropofol disodium on concentrations of concomitantASMs. Such analyses could provide useful information as to the potentialfor drug-drug interactions requiring further evaluation in thesubsequent development of fospropofol disodium in the treatment andprevention of epileptic seizures.

Photoparoxysmal Response

Descriptive statistics will be presented including the means andstandard deviations of photosensitivity range for each subject, for eachday. Graphical displays of the data for each subject will allowexploration of inter- and intra-subject variability.

Example A20—Study A20

A Multicenter, Randomized, Double-Blind, Placebo-Controlled,Dose-Finding Study of Fospropofol disodium in the Acute Treatment ofModerate to Severe Migraine Headache

-   -   Study Drug Fospropofol Disodium    -   Study Phase and Type Phase 2—Multicenter, Randomized,        Double-Blind, Placebo-Controlled, Single-dose, Dose-Finding        Study of FOSPROPOFOL DISODIUM in the Acute Treatment of Moderate        to Severe Migraine Headache    -   Objectives Primary Objectives        -   To assess the dose response of 2-hour freedom from pain            across a range of fospropofol disodium doses.        -   To assess the dose response of 2-hour freedom from the            subject's most bothersome symptom (MBS) for the treated            headache across a range of fospropofol disodium doses.        -   To evaluate the safety and tolerability of various doses of            fospropofol disodium in the acute treatment of migraine.        -   Secondary Objectives        -   To assess the dose response of 2-hour pain relief (PR)            across a range of fospropofol disodium doses.        -   To assess the dose response of freedom from nausea/vomiting,            freedom from photophobia, and freedom from phonophobia (by            symptom) at 2 hours post dose.        -   To assess the dose response of sustained freedom from pain            from 2-24 hours and from 2-48 hours post-dose. Sustained            freedom from pain is defined as pain free at 2 hours            post-dose, with no administration of any rescue medication            and with no recurrence of headache pain            (mild/moderate/severe) during the respective period after            dosing.        -   To assess the dose response of sustained freedom from the            MBS from 2-24 hours and from 2-48 hours post-dose. Sustained            freedom from the MBS is defined as absence of the MBS at 2            hours post dose, with no administration of any rescue            medication and with no recurrence of the MBS during the            respective period after dosing.        -   To assess the dose response of sustained pain relief from            2-24 hours and from 2-48 hours post-dose. Sustained pain            relief is defined as pain relief at 2 hours post dose, with            no administration of any rescue medication and with no            recurrence of moderate/severe headache pain during the            respective period after dosing.        -   To assess the dose response of sustained freedom from            symptoms (nausea/vomiting, photophobia, or phonophobia), by            symptom, from 2-24 hours and from 2-48 hours post-dose.            Sustained freedom from a symptom is defined as symptom free            for that symptom at 2 hours post dose, with no            administration of any rescue medication and with no            recurrence of that symptom during the respective period            after dosing.    -   Study Design This is a Phase 2, multicenter, randomized,        double-Blind, placebo-controlled, parallel-group, single-dose        study of fospropofol disodium in the acute treatment of moderate        to severe migraine headache in adult women and men with a        history of episodic migraine with or without aura, diagnosed        based on the International Classification of Headache Disorders,        edition 3 (ICHD-3). The migraine diagnosis will be confirmed in        a virtual (online) interview with a specialist in headache        medicine. The study is planned to complete approximately 1600        subjects.        -   After screening to confirm eligibility, subjects will be            randomized to receive a single dose of either fospropofol            disodium at one of 3 dose levels or placebo to be            self-administered on an outpatient basis when the subject            experiences a qualifying migraine headache. Dosing must            occur within 4 hours after onset of the migraine pain.            Dosing must occur within 60 days after randomization.        -   Subjects will report headache pain (presence and severity)            and associated migraine symptoms (present or absent) within            10 minutes before dosing, and at 0.5, 1, 1.5, 2, 4, 6, 12,            24, and 48 hours after dosing using an electronic diary.            Subjects will also report adverse events throughout.            Subjects will be permitted to self-administer rescue            medication if needed, but they will be strongly encouraged            to avoid rescue medication until after 2 hours after dosing.        -   Participants will be considered to have completed the study            if they have self-administered study drug within 60 days            after randomization and completed all procedures listed in            the Schedule of Events including the follow-up clinic visit            at Day 6±2 days and the follow-up telephone interview at Day            15±2 days. (The day of treatment is defined as Day 1.)    -   Justification for Dose Selection of the doses for this study is        based on the results of the prior Phase 1a study, Study A16, the        prior Phase 1b study, Study A17, and the pharmacokinetic        bridging study (tablet to capsule comparison) Study A18.    -   Safety Committee A Safety Review Committee will be established        to review periodic summaries of safety data from this study and        to provide consultation as outlined in the Safety Committee        Charter. The Safety Review Committee will be blinded to the        treatment assignment.    -   Subject Selection The study is planned to enroll a sufficient        number of subjects so as to complete approximately 1600        subjects. Because the prevalence of migraine headaches is higher        in women than in men, efforts will be made to enroll at least        50% women.        -   Subjects must meet the general inclusion and exclusion            criteria listed below (Inclusion Criteria and Exclusion            Criteria) at screening in order to be randomized in the            study. To be eligible for treatment with study, the subject            must experience a qualifying headache (see Qualifying            Headache below) and adhere to study restrictions specific to            the period between randomization and end of study            participation (see Post-randomization Study Restrictions            below).    -   Inclusion Criteria Subjects must meet all of the following        criteria at screening to be enrolled in the study:        -   1. Written informed consent approved by the Institutional            Review Board (IRB) given before any study-related procedures            are performed        -   2. Male or female, ≥18 and ≤55 years of age at the time of            signed informed consent, with a body mass index (BMI) ≥18.0            and ≤35 kg/m² and body weight ≥50.0 kg for men and ≥45.0 kg            for women.        -   3. History of episodic migraine consistent with a diagnosis            of migraine with or without aura according to the ICHD-3            criteria, plus the following:            -   a) Migraine attacks present for >1 year with age of                onset <50 years.            -   b) History of 2 to 8 migraine attacks with moderate or                severe pain per month (at least 8 hours in duration if                untreated or any duration if treated) in each of the 3                months prior to the screening visit.        -   4. Subjects who are treated with drugs intended for migraine            prophylaxis or drugs prescribed for a purpose other than            migraine prophylaxis but with a potential prophylactic            effect on migraine are eligible if they have been on a            stable regimen for at least 3 months prior to screening and            meet other inclusion/exclusion criteria.        -   5. Female subjects must fulfill at least one of the            following:            -   a) Surgically sterile, defined as women who have had a                tubal ligation, hysterectomy, or bilateral oophorectomy                at least 6 months prior to screening.            -   b) Post-menopausal, defined as absence of menses for at                least 12 months prior to screening.            -   c) Women who are sexually active and at risk for                pregnancy must agree to avoid pregnancy and use a                medically acceptable method of contraception from at                least 30 days prior to screening until 30 days after                study drug administration.            -   Medically acceptable methods of contraception include                hormonal contraception, hormonal or non-hormonal                intrauterine device, double barrier method (simultaneous                use of male condom with intravaginally applied                spermicide and diaphragm or cervical cap), or male                partner vasectomy at least 6 months previously. Complete                abstinence alone can be used as a method of                contraception.        -   6. Male subjects who are not vasectomized for at least 6            months, and who are sexually active with a non-sterile            female partner (see definitions of surgically sterile and            post-menopausal above) must be willing to use one of the            following acceptable contraceptive methods throughout the            study and for 90 days after the study drug administration            (Complete abstinence alone can be used as a method of            contraception):            -   a) Simultaneous use of male condom and, for the female                partner, intrauterine contraceptive device with or                without hormone release (placed at least 4 weeks                previously)            -   b) Simultaneous use of male condom and, for the female                partner, hormonal contraception            -   c) Simultaneous use of male condom and, for the female                partner, intravaginally applied spermicide with                diaphragm or cervical cap        -   7. Able to comprehend the nature of the study, capable of            giving written informed consent, and able to communicate            effectively with clinic staff (as assessed by the            investigator)        -   8. Available to volunteer for the entire study duration and            willing to adhere to all protocol requirements, including            the post-randomization restrictions (see Post-Randomization            Restrictions below)        -   9. Agree not to post any information related to the study on            any website or social media site (e.g., Facebook, Twitter,            LinkedIn, Google+, etc.) until the entire trial has been            completed        -   10. Willing to forgo rescue medicine for at least 2 hours            after administration of study drug (see Rescue Medication)    -   Exclusion Criteria Subjects to whom any of the following        criteria apply at screening will be excluded:        -   1. History of hemiplegic migraine (at any time in the past).        -   2. History of headaches of any type occurring on ≥15            days/month during any of the 3 months prior to screening.        -   3. If subject has coexisting history of tension-type            headaches and migraine, inability to distinguish between            tension-type headaches and migraine.        -   4. In the investigator's judgment, overuse of medication for            migraine or other conditions, defined as use of any of the            following in any of the 3 months prior to screening:            -   a) Narcotics (opioids) ≥5 days/month (Opioids are                allowed as second-line treatment as long as they were                used <5 days/month), or            -   b) Sedative-hypnotic drugs, (e.g., benzodiazepines,                barbiturates, sleeping aids, combination analgesic                medications containing butalbital) ≥8 days/month, or            -   c) Triptans (e.g., sumatriptan, naratriptan,                almotriptan, etc.) or ergotamine ≥8 days/month, or            -   d) Simple analgesics (e.g., aspirin, NSAIDs,                acetaminophen, caffeinated analgesic combinations) ≥12                days/month (Occasional use of topical products without                significant systemic absorption is permitted.)            -   e) Anti-emetics, diphenhydramine ≥10 days/month.            -   f) Gepants: calcitonin gene-related peptide (CGRP)                receptor antagonists (e.g., ubrogepant, rimegepant) ≥10                days/month.            -   g) Ditans (lasmiditan) ≥10 days/month.            -   h) Herbal supplements and natural health products used                for acute treatment of migraine 10 days/month.        -   5. History of any of the following:            -   a) Clinically significant history of endocrine,                cardiovascular, pulmonary, hematologic, immunologic,                gastrointestinal, renal, hepatic, or metabolic disease;                or psychiatric conditions, major depression, dementia,                or significant neurological disorders other than                migraine that in the investigator's judgment would                interfere with the study, or            -   b) Active malignancy of any type or a history of                malignancy within the last 5 years (except basal cell                carcinoma of the skin that has been excised at least 12                weeks prior to study start), or            -   c) Major surgery within 6 months prior to screening,                unless the investigator deems the subject eligible                (minor surgery performed 4 or more weeks prior to                screening would not be a reason for exclusion), or            -   d) Pain syndrome other than migraine that in the                investigator's judgment would interfere with the study,                or            -   e) Diagnosis of sleep apnea, or            -   f) Any other medical condition that, in the opinion of                the investigator or the Sponsor, may be potentially                associated with an increased risk to the subject from                study drug or to participation in the study.        -   6. Subjects who have any of the following at screening:            -   a) Clinically significant abnormality at physical                examination (in the judgment of the investigator), or            -   b) Clinically significant ECG abnormalities (in the                judgment of the investigator), or            -   c) Vital sign abnormalities (systolic blood pressure                [BP]<90 mmHg or >145 mmHg, diastolic blood pressure <55                mmHg or >95 mmHg, or heart rate [HR]<50 bpm or >110                bpm), or            -   d) Oxygen saturation by oximetry (SpO₂)<93%, or            -   e) Hemoglobin <135 g/L for men or <120 g/L for women            -   r) Clinically significant abnormal laboratory test                results (out of the study laboratory's acceptable range,                unless out-of-range values are deemed by the                investigator to be not clinically significant).        -   7. Subjects with a history of any of the following:            -   a) Significant alcohol abuse within 1 year prior to                screening or regular use of alcohol within 6 months                prior to screening (more than 14 units of alcohol per                week [1 unit=150 mL of wine, 360 mL of beer, or 45 mL of                40% alcohol]), or            -   b) Significant drug abuse or use of cocaine,                phencyclidine [PCP], crack, opioid derivatives including                heroin, or amphetamine derivatives, or similar drugs                within 1 year prior to screening, or significant use of                marijuana or tetrahydrocannabinol [THC]-containing                products that in the investigator's judgment is                medically significant in that it would impact the safety                of the subject or the interpretation of the study                results.        -   8. Subjects who have any of the following at screening:            -   a) A positive alcohol breath test or            -   b) A positive urine drug screen (unless consistent with                an ongoing prescription drug as documented by the                investigator) (Note that detectable levels of marijuana                (THC or metabolites) in the urine drug screen are not                exclusionary if in the investigator's documented                opinion, the positive test does not signal a clinical                condition that would impact the safety of the subject or                interpretation of the study results.)        -   9. Women who are pregnant (have a positive urine pregnancy            test at screening) or who are nursing        -   10. Subjects who have a history of severe allergic reactions            (e.g., anaphylactic reactions, angioedema),            hypersensitivity, or idiosyncratic reaction to fospropofol,            propofol, or related substances.        -   11. Subjects who have participated in an interventional            clinical research study involving:            -   a) Administration of an investigational or marketed drug                or device within 30 days prior to screening, or            -   b) Administration of a biological product in the context                of a clinical research study within 90 days prior to                screening.                -   (Concomitant participation in an investigational                    study involving no drug, device or other                    intervention is permitted, provided obligations                    associated with the concomitant participation are                    not expected to interfere with procedures and                    obligations of the present study.)        -   12. Employees or immediate families (defined as spouse,            significant-other, parent, child, or sibling, whether            adopted or biologic) of an employee of Epalex Corporation,            its affiliates, or partners; investigator or study center            personnel directly affiliated with this study and/or their            immediate families.        -   13. Subjects who have a condition or are in a situation that            in the investigator's opinion may put the subject at            significant risk, may confound the study results, or may            interfere significantly with the subject's participation in            the study.        -   14. Score of >0 on the Sheehan Suicidality Tracking Scale            (S-STS) for a recall period of 30 days prior to screening.    -   Eligibility for Dosing: Qualifying Headache To qualify for        treatment with study drug, the headache must meet the following        criteria:        -   1. Subject was free of migraine symptoms for at least 48            hours before the start of symptoms of the migraine headache            to be treated (and did not take any medications for the            acute treatment of migraine during this period).        -   2. Subject must not have consumed alcohol within 24 hours            prior to dosing.        -   3. Subject must not have taken any antacid, proton pump            inhibitor, or H2 blocker within 24 hours prior to dosing.        -   4. Time between onset of the pain of the migraine headache            to be treated and actual time treatment must be less than 4            hours.        -   5. Moderate or severe pain intensity (2 or 3 on a 4-point            Likert scale where 0=none, 1=mild, 2=moderate, 3=severe)        -   6. Has at least 1 of the following characteristics:            unilateral location, throbbing (pulsating), or aggravated by            routine physical activity.        -   7. Associated with at least 1 of the following symptoms:            nausea/vomiting, photophobia, or phonophobia assessed        -   8. Within 10 minutes before dosing:            -   a) Moderate or severe pain intensity (2 or 3 on a                4-point Likert scale where 0=none, 1=mild, 2=moderate,                3=severe).            -   b) Presence of at least 1 symptom (nausea/vomiting,                photophobia, or phonophobia).    -   Post-randomization Study Restrictions The following restrictions        specific to the period after randomization until end of study        must be met for treatment of a migraine with Restrictions        fospropofol disodium to occur.        -   Medications Permitted with Restrictions        -   If the subject experiences a migraine headache where study            treatment is not feasible or practicable, the following            medications for acute migraine treatment are allowed after            randomization, as agreed with the investigator at screening,            provided the following restrictions to prevent overuse are            met and provided the subject has not taken them within 48            hours prior to taking study drug (see Point 3 under            Restricted and prohibited substances or products below):            -   1. Narcotics (opioids) as second-line treatment only: No                more than 4 days/month or in the 30 days prior to                dosing.            -   2. Sedative-hypnotic drugs, (e.g., benzodiazepines,                barbiturates, sleeping aids, combination drugs                containing butalbital): No more than 7 days/month or in                the 30 days prior to dosing.            -   3. Triptans (e.g., sumatriptan, naratriptan,                almotriptan, etc.) or ergotamine: No more than 7                days/month or in the 30 days prior to dosing.            -   4. Analgesics, alone or in a combination product (e.g.,                aspirin, NSAIDs, acetaminophen, caffeinated analgesic                combinations): No more than 11 days/month or in the 30                days prior to dosing.            -   5. Anti-emetics, diphenhydramine. No more than 9                days/month or in the 30 days prior to dosing.            -   6. Gepants: CGRP receptor antagonists (e.g., ubrogepant,                rimegepant). No more than 9 days/month or in the 30 days                prior to dosing.            -   7. Ditans: lasmiditan. No more than 9 days/month or in                the 30 days prior to dosing.            -   8. Herbal supplements and natural health products used                for acute treatment of migraine. No more than 9                days/month or in the 30 days prior to dosing.        -   Restricted and prohibited substances or products            -   9. Alcohol-based products are to be restricted as                follows:                -   a) No more than 14 units of alcohol per week [1                    unit=150 mL of wine, 360 mL of beer, or 45 mL of 40%                    alcohol])                -   b) Subject is not to administer study drug they have                    consumed alcohol within 24 hours prior to dosing.                    (See Eligibility for Dosing: Qualifying Headache.)            -   10. The following products are not permitted at any time                during study participation (from randomization until                study completion [after the Day 15 telephone call]):                -   Cocaine, phencyclidine [PCP], crack, opioid                    derivatives including heroin, amphetamine                    derivatives, or similar drugs. Urine drug screen                    must be negative at screening. (Foods containing                    poppy seeds should be avoided prior to screening                    because they may interfere with results of the urine                    drug screen.) Note that detectable levels of                    marijuana (THC or metabolites) in the urine at                    screening are not exclusionary if in the                    investigator's documented opinion, the positive test                    does not signal a clinical condition that would                    impact the safety of the subject or interpretation                    of the study results and documents that the subject                    affirms that they will not administer study drug if                    they have used marijuana or any THC-containing                    product within the 48 hours prior to dosing.            -   11. FOSPROPOFOL DISODIUM dosing is not to be performed                if the subject has taken any of these medications within                the 48 hours prior do dosing with study drug:                -   a) Narcotics (opioids), sedative-hypnotic drugs,                    (e.g., benzodiazepines, barbiturates, sleeping aids,                    combination drugs containing butalbital).                -   b) Triptans (e.g., sumatriptan, naratriptan,                    almotriptan, etc.) or ergotamine.                -   c) Analgesics, alone or in a combination product                    (e.g., aspirin, NSAIDs, or acetaminophen).                -   d) Anti-emetics, diphenhydramine.                -   e) Gepants: CGRP receptor antagonists (e.g.,                    ubrogepant, rimegepant).                -   f) Ditans: lasmiditan.                -   g) Herbal supplements and natural health products                    used to treat migraine.                -   h) Marijuana or THC-containing products                -   i) FOSPROPOFOL DISODIUM dosing is not to be                    performed if the subject has taken any of these                    medications within the 24 hours prior to dosing with                    study drug:                -   j) Any antacid                -   k) Any proton pump inhibitor                -   l) Any H2 blocker        -   Other Restrictions        -   Dosing is not to be performed if any of the following            conditions apply.            -   1. Events within 30 days prior to clinic check-in:                -   a) Significant illness or any surgical procedure                -   b) Subject donated plasma or blood            -   2. Any vaccination (e.g., COVID-19 vaccination,                influenza) within 10 days prior to dosing            -   3. Headaches occurring on ≥15 days in the month prior to                dosing with study drug            -   4. Abnormal diet patterns (for any reason) during the 4                weeks preceding dosing, including fasting, high protein                diets etc.            -   5. Conditions or situations arising since clinic                enrollment that in the investigator's opinion, may put                the subject at significant risk or may confound the                study results.        -   Permitted Throughout the Study            -   1. Standard migraine prophylactic medications and other                medications with a prophylactic effect on migraines are                permitted as prescribed, provided that the regimen                (drug, route, dose, frequency) has been stable for at                least 3 months prior to the screening visit and no                changes in the regimen are expected (or made) during                study participation. Prophylactic medications may not be                started during the study. Examples of permitted                prophylactic drugs are beta-blockers, tricyclic                antidepressants, topiramate, and valproic acid.                Botulinum toxin (approved only for chronic migraine) is                prohibited. Nurtec ODT (Rimegepant) approved for acute                treatment of migraine as well as prophylaxis is                prohibited. Phenytoin, and carbamazepine are prohibited.                Among other drugs currently approved for migraine                prophylaxis, the following are permitted if the regimen                has been stable during the three months prior to                screening: Aimovig (erenumab), Ajoy (fremanezumab),                Emgality (galcanezumab), Vyepti (eptinezumab).            -   2. Hormonal contraception and routine use of                over-the-counter (OTC) multivitamins for general health                are permitted throughout the study.            -   3. Other prescription medications and OTC medicines are                permitted if medically necessary as agreed with the                investigator on a case-by-case basis at screening.            -   4. Herbal supplements and health products are permitted                if agreed with the investigator on a case-by-case basis                at screening.    -   Rescue Medication Rescue medication is defined as any treatment        for migraine (as agreed between subject and investigator at        screening) that is self-administered by the subject in the        48-hour interval following dosing with study drug. Rescue        medication may be self-administered at any time after dosing        with study drug if additional medication for acute treatment of        migraine pain or associated symptoms is necessary. However,        subjects will be strongly encouraged to avoid administration of        rescue medication earlier than 2 hours after dosing. The subject        should record the 2-hour assessments of headache pain,        associated symptoms, most bothersome symptom, and assessment of        functional disability before taking any rescue treatment. If        rescue treatment is needed at any time between 2 hours and 48        hours after dosing and near the time of a scheduled assessment,        the scheduled assessment be completed before the administration        of rescue treatment.        -   The investigator and subject must agree at screening on the            appropriate rescue therapy for the subject. Subjects will            supply their own rescue medication and use it according to            label. Rescue treatment may be self-administered on more            than one occasion after dosing but dose and frequency must            be consistent with product labelling. Any administration of            rescue medication including drug, route, quantity, and time            of dosing must be reported in the electronic diary.        -   Selection of the agreed upon rescue treatment for each            subject may be guided by treatment that was effective for            the subject in the past. First-line rescue therapy may            include an analgesic and/or acute migraine medication and            will not include narcotics. If necessary, a second-line            rescue therapy may be agreed upon at the investigator's            discretion.        -   The following products may be agreed upon between subject            and investigator at screening to be used as rescue            medication if required in the clinic after dosing with study            drug:            -   1. Analgesics, alone or in a combination product,                including acetaminophen, aspirin, or NSAIDs.            -   2. Triptans (e.g., sumatriptan, naratriptan,                almotriptan).            -   3. Gepants (CGRP antagonists, e.g., ubrogepant                (Ubrelvy®), rimegepant (Nurtek®).            -   4. Ditans (e.g., lasmiditan (Reyvow®)).        -   Because of the potential for additive cardiorespiratory            effects when narcotic analgesics and sedative-hypnotic            agents (e.g., opiates, benzodiazepines, barbiturates,            sleeping aids, combination drugs containing butalbital) are            administered concomitantly with FOSPROPOFOL DISODIUM, these            medications are not recommended as rescue therapy after            FOSPROPOFOL DISODIUM dosing. Prescription anti-emetics,            including metoclopramide, prochlorperazine, chlorpromazine,            as well as OTC drugs sometimes helpful for nausea, such as            dimenhydrinate, meclizine, and diphenhydramine, are            associated with sedation and should be avoided as rescue            treatment until at least 4 hours after treatment with            FOSPROPOFOL DISODIUM.    -   Study Drug and Dosage Form FOSPROPOFOL DISODIUM is formulated        for oral administration in an appropriate number of tablets.        Each tablet contains 200 mg of fospropofol disodium (uncorrected        for sodium content) and inactive ingredients. It is possible        that tablets containing smaller amounts of FOSPROPOFOL DISODIUM        may also be used.    -   Dose Level Subjects will be randomized 1:1:1:1 to receive one of        four double-blind treatments comprising placebo and 3 dose        levels of FOSPROPOFOL DISODIUM. See Randomization, below.    -   Administration of Study Drug Dosing must occur within 4 hours        after onset of migraine pain. The study drug will be        administered with water at ambient temperature in the amount of        approximately 240 mL [8 oz]. Except for water administered with        the study drug, fluids will not be permitted from dosing until 1        hour after dosing (see Study Restrictions). Fluids will be        permitted ad lib thereafter.        -   As a safety precaution, subjects will be instructed to            remain seated or semi-reclined for 2 hours after            administration of study drug.        -   Subjects are permitted to sleep (in a semi-reclined            position) after administration of study drug but requested            to record in the electronic diary assessments of headache            pain, associated migraine symptoms, and level of functional            disability predose and at intervals after dosing.    -   Randomization Subjects will be randomly allocated in blocks of 4        subjects to 1 of 4 treatments (A, B, C, or D) as shown below:

Number mg Number of Treatment fospropofol Tablet of Active PlaceboAssignment disodium Strength Tablets Tablets A Placebo 0 0 0 3 BFospropofol 200 200 1 2 disodium, Dose Level 1 C Fospropofol 400 200 2 1disodium, Dose Level 2 D Fospropofol 800 200 4 0 disodium, Dose Level 3Placebo tablets will be identical in appearance to the active tablets.

-   -   -   Placebo tablets will be identical in appearance to the            active tablets.

    -   Screening Procedures Screening procedures will comprise written        informed consent and review of inclusion/exclusion criteria,        including demographic data; body measurements (height, weight);        medical and migraine history; medication history (including drug        allergies); 12-lead ECG; pulse oximetry; vital signs (BP, HR,        RR, temperature), safety laboratory assessments (hematology,        blood chemistry, urinalysis, urine drug screen, alcohol breath        test, serum pregnancy test for women of child bearing potential;        complete physical examination, and the Sheehan Suicidality        Tracking Scale.        -   Migraine history will be obtained by subject interview and            will include age of onset and time since first attack;            estimated frequency of migraine episodes during the prior 3            months, including frequency of episodes classified as            moderate or severe; history of migraine-associated symptoms            (nausea/vomiting, photophobia, phonophobia, or other            symptoms); the usual most bothersome symptom            (nausea/vomiting, photophobia, or phonophobia);            characteristic features of episodes (unilateral vs bilateral            location, pulsating quality, pain intensity, aggravation by            or causing avoidance of routine physical activity); presence            and features of aura, if any; and history of headache types            other than migraine and subject's ability to distinguish            between migraine and tension-type headaches.        -   Medication history will be obtained by interview and will            include history of migraine-related medications during the 3            months prior to screening. Migraine-related medications            include medications (if any) used for first- and/or            second-line acute treatment of migraine and medications used            for migraine prophylaxis or those that have prophylactic            effect on migraine. History of other medications will be            recorded for the period 30 days prior to screening.        -   Medications permitted for use during the course of study            will be reviewed, recorded, and approved at screening by the            investigator (in consultation with the Sponsor as needed or            requested). Such medications include acute migraine            treatment to be used if treatment with study drug is not            feasible within 4 hours after onset of headache pain.            Medications used for migraine prophylaxis or those that have            prophylactic effect on migraine must have been stable            (consistent with respect to drug, route, dose, and dosing            regimen) for at least 3 months prior to screening (see            Post-Randomization Study Restrictions).        -   The investigator and subject are to agree at screening on an            appropriate rescue medication(s) to be used if needed after            dosing with study drug (see Rescue Medication).        -   Subjects who give written informed consent and meet            inclusion/exclusion criteria will be randomized. Randomized            subjects will receive instructions regarding restrictions            during study participation, identification of a qualifying            headache, as well as instructions for administration of            study drug and necessary precautions.

    -   Post-randomization Period Randomized subjects will be asked to        self-administer study drug as soon as possible when they        experience a qualifying migraine, i.e., migraine pain of at        least moderate severity together with at least one associated        symptom (nausea, photophobia, phonophobia) as dosing must occur        within 4 hours after onset of migraine pain. If treatment is not        feasible or practicable within 4 hours after the onset of        migraine pain, subjects should use their usual headache        medication as agreed at screening and within the parameters        noted in the Post-Randomization Study Restrictions. This        situation may arise, for example, if the headache is not a        qualifying migraine or if onset of symptoms occurs when family        or work circumstances make it impracticable for the subject to        self-administer study drug within the 4-hour time frame. In such        cases, the subject should attempt to self-administer study drug        for the treatment of their next qualifying migraine headache.        -   Treatment of a qualifying headache is to occur within 60            days after randomization. Clinic staff are to remain in            telephone contact with subjects as needed (at least monthly)            to identify and address any barriers that may prevent            subjects from treating a qualifying headache.        -   If a randomized subject does not self-administer study drug            within 60 days after randomization, this situation is to be            classified as “failure to dose.” If possible, reasons for            failure to dose within 60 days should be ascertained and            recorded using the following checklist of potential issues:            lack of moderate to severe headaches, work circumstances,            family circumstances, lack of adherence to            post-randomization study restrictions, or other reasons.

    -   Prior to Self-administration of Study Drug (Day 1) The subject        is to perform the following procedures before        self-administration of study drug:        -   1. Assess the presenting headache and associated symptoms to            determine whether it is a qualifying headache (See            Eligibility for Dosing, Qualified Headache)        -   2. Ensure that agreed upon rescue drug(s) is/are available        -   3. For women of child-bearing potential, perform urine            pregnancy test (must be negative before dosing)        -   4. Record time and nature of last meal or food intake,            including beverages.        -   5. Record in the electronic diary pre-dose (within 10            minutes prior to dosing) severity of qualifying headache            pain, presence/absence of associated symptoms            (nausea/vomiting, photophobia, and phonophobia), and level            of functional disability, and identify and record from among            the associated symptoms the most bothersome symptom for the            current headache episode.

    -   Following Self-administration of Study Drug (Day 1-Day 3) The        subject will be instructed that the study drug may be associated        with some degree of sedation. Therefore, the subject should        remain seated or semi-reclined for 2 hours after administration        of study drug. The subject should refrain from driving or        operating heavy equipment for 24 hours after dosing.        -   The subject will record in the electronic diary the            assessments as scheduled in the Schedule of Events including            severity of headache pain, presence/absence of the most            bothersome symptom, presence/absence of the other associated            symptoms, and level of functional disability. These            assessments will be recorded in the electronic diary at            intervals until 48 hours after dosing. The quality-of-life            assessment will be completed at approximately 24 hours after            dosing. The subject will record an assessment of            satisfaction with study drug at 48 hours. Subjects will            record any adverse events in the electronic diary.        -   Rescue treatment (treatment for migraine self-administered            within 2 to 48 hours after dosing) as agreed with the            investigator at screening may be used at any time after the            2-hour assessment of headache pain, symptoms, and functional            disability. The dose, route, and frequency of administration            must be consistent with the product labelling. Each use of            rescue medication (drug, dose, route, and time of            self-administration) must be recorded in the electronic            diary (See Rescue Medication).        -   As soon as convenient after dosing, the subject will contact            the study site to schedule the Post-treatment Visit (Visit            2). The post-treatment visit should be scheduled on Day 6±2            days, i.e., on Day 4, 5, 6, 7, or 8 (with the day of dosing            defined as Day 1).

    -   Post-treatment Visit (Visit 2) Electronic diary entries will be        reviewed with the subject. The following procedures will be        carried out at Visit 2, the post-treatment visit. Sheehan STS,        Safety laboratory assessments (hematology, blood chemistry,        urinalysis, serum pregnancy test in women of child-bearing        potential), vital signs (BP, HR, RR, temperature), pulse        oximetry, 12-lead ECG, headache assessment, physical examination        and neurological examination, recording of adverse events (AEs).        The subject will complete a work and productivity questionnaire.        -   Arrangements for the follow-up telephone interviews will be            made.

    -   Follow-up Telephone Interview A follow-up telephone interview        will be scheduled at approximately 14 days post-treatment for        subjects to report and occurrence of any AEs since treatment.

    -   Safety Procedures and Assessments. Medical Surveillance and AE        Monitoring        -   Subjects will record adverse events from the time of            randomization until the follow-up telephone interview            approximately two weeks after dosing (See Overall Schedule            of Events) or until discontinuation if the subject withdraws            prematurely.        -   Safety data will be evaluated on an ongoing basis by the            Safety Review Committee to ensure it is safe to continue            study enrollment and treatment.        -   Safety parameters, including physical examination,            laboratory results and ECG, will be evaluated by the            investigator in the context of clinical trial safety. Any            abnormal measurement is to be repeated if judged necessary            by the investigator.        -   12-Lead ECG        -   A 12-lead ECG will be performed at screening (Visit 1) and            at the post-treatment visit (Visit 2).        -   Safety Laboratory Assessments        -   Hematology, serum chemistry, and urinalysis will be assessed            at screening (Visit 1) and at the post-treatment visit            (Visit 2).        -   A urine drug screen and alcohol breath test will be            performed at screening (Visit 1). For women of child-bearing            potential, a urine pregnancy test will be performed by the            subject prior to dosing. A serum pregnancy test will be            performed at screening and at the post-treatment visit            (Visit 2).        -   Physical Examination        -   A complete physical examination will be performed at            screening (Visit 1) and at the post-treatment visit (Visit            2).        -   Sheehan Suicidality Tracking Scale        -   The Sheehan Suicidality Tracking Scale will be administered            at the screening visit (Visit 1, and at the and at the            post-treatment visit (Visit 2).

    -   Measures of Clinical Course Headache pain and associated        migraine symptoms (nausea/vomiting, photophobia, and        phonophobia) will be recorded as migraine-related events.        Headache pain will be rated on a 4-point Likert scale (0=none,        1=mild, 2=moderate, 3=severe). Associated migraine symptoms        (nausea/vomiting, photophobia, and phonophobia) will be        classified as either present or absent.        -   The subject will record in the electronic diary the            assessments as scheduled including severity of headache            pain, presence/absence of the most bothersome symptom,            presence/absence of the other associated symptoms, and level            of functional disability. These assessments will be recorded            in the electronic diary at intervals until 48 hours after            dosing. The quality-of-life assessment will be completed at            approximately 24 hours after dosing. The subject will record            an assessment of satisfaction with study drug at 48 hours.            The subject will record in the electronic diary the use of            any concomitant medications from the time of dosing until 48            hours thereafter. Concomitant medications will be recorded            to include identification of the drug, route, dose, and time            of administration.        -   The subject will complete a work and productivity            questionnaire at the post-treatment visit (Visit 2).

    -   Adverse Events Subjects will be instructed record any potential        AEs, i.e., untoward medical symptoms and/or events that may        arise from the time of randomization until the follow-up        telephone interview (to be conducted approximately 2 weeks after        administration of study drug including time of onset, duration,        and severity.        -   Treatment-emergent adverse events (TEAEs) are defined as the            reported AEs that first occurred or worsened after            administration of the study drug. Adverse events will be            reviewed by the investigator at Visit 2 and again at the            follow-up telephone interview. The incidence, seriousness,            severity, duration, and relation to study drug of all TEAEs            will be reviewed and recorded by the investigator.        -   Some degree of sedation is an expected and potentially            therapeutic effect of the study drug. Although sedation,            including events described as feeling “drowsy,” “sleepy,”            “relaxed,” etc., will be expected, such terms if expressed            by the subject will be recorded as AEs, and severity will be            rated by the site investigator as mild, moderate, or severe.        -   Worsening or recurrence of migraine pain or related migraine            symptoms (nausea/vomiting, photophobia, phonophobia) from            dosing until 48 hours after dosing will be recorded as            migraine-related events and will not be recorded as AEs.

    -   Statistical Considerations A complete description of the        statistical analyses to be performed for the safety,        tolerability, and clinical course will be presented in a        Statistical Analysis Plan (SAP).        -   Safety and Tolerability        -   Safety and tolerability data will be reported using            descriptive statistics. Summary statistics for TEAEs will be            reported. Changes from baseline values on physical            examination, and clinical laboratory parameters, and ECG            will be reported.        -   Clinical Course        -   Summary statistics will be reported by treatment group for            the following assessments:            -   1. Headache pain (on the Likert scale) at all timepoints                (See Schedule of Events)            -   2. Presence/Absence of the most bothersome symptom (MBS)                at all timepoints            -   3. Presence/Absence of each migraine-related symptom                (nausea/vomiting, photophobia, or phonophobia), by                symptom, at all timepoints            -   4. Level of functional disability at all timepoints            -   5. Use of rescue medication at all time points            -   6. Quality of life assessments (2-24 hours) assessed at                24 hours after dosing            -   7. Assessment of satisfaction with Study Drug assessed                at 48 hours after dosing            -   8. Work and productivity loss questionnaire assessed at                Visit 2 (Day 6±2 days) where the day of dosing is                defined as Day 1.        -   Summary statistics by treatment group will be presented for            the following specified outcomes:        -   (1) Proportion of subjects reporting no headache pain at 2            hours        -   (2) Proportion of subjects reporting the absence of the most            bothersome symptom (MBS) at 2 hours        -   (3) Proportion of subjects reporting pain relief (change            from severe/moderate to mild/absent) at 2 hours.        -   (4) Proportion of subjects reporting absence of each            migraine-related symptom (nausea/vomiting, photophobia, or            phonophobia), by symptom, at 2 hours.        -   (5) Proportion of subjects reporting sustained freedom from            headache pain at 24 hours, and at 48 hours.        -   (6) Proportion of subjects reporting sustained of absence of            the MBS at 24 hours, and at 48 hours.        -   (7) Proportion of subjects reporting pain sustained pain            relief at 24 hours, and at 48 hours        -   (8) Proportion of subjects reporting sustained absence of            each migraine-related symptom (nausea/vomiting, photophobia,            or phonophobia), by symptom, at 24 hours, and at 48 hours        -   In addition, summary statistics by treatment group will be            provided for quality of life (assessed at 24 hours            post-dose), satisfaction with study drug (assessed at 48            hours post-dose), and work and productivity loss (assessed            at Visit 2, approximately 2 weeks post-dose).

Example B—Acidified Tablets Example B1: Dissolution and pH Studies

Fospropofol Disodium tablets, 600 mg (label claim; l.c.), weremanufactured for dissolution testing and use in a pharmacokineticsstudy. A total of three tablets for each lot were weighed prior totesting.

TABLE B1 Acidified Tablets - Compositions A1 A2 A3 A4 Composition mg %w/w mg % w/w mg % w/w mg % w/w Fospropofol 666.9* 42.96 666.9* 42.96666.9* 56.43 666.9* 65.18 Disodium hydrate* Polyplasdone 77.6 5.00 77.65.00 59.1 5.00 51.2 5.00 XL Magnesium 7.8 0.50 7.8 0.50 5.9 0.50 5.10.50 Stearate Citric Acid, 800.0 51.54 monohydrate Ascorbic 800.0 51.54Acid Tartaric Acid 450.0 38.07 Malic Acid 300.0 29.32 Total 1552.3100.00 1552.3 100.00 1181.9 100.00 1023.2 100.00 *equivalent to 600 mgfospropofol disodium adjusted for water content.

Dissolution studies were performed under the conditions shown in TableB2 (n=3 vessels, 300-mL media volume and a single tablet per vessel).Analyses were performed by HPLC under the conditions shown in Table B3.

TABLE B2 Conditions for Dissolution Studies Conditions SettingDissolution Medium 0.1 NHCl de-aerated Apparatus USP apparatus II(rotating paddles) Vessel Volume 300 mL Temperature 37.0° C. ± 0.5° C.Rotation Speed 50 RPM (200 RPM from 60-75 or 60-90 minutes) SampleVolume 1.5 mL Sample Times 5, 10, 15, 20, 25, 30, 40, 45, and 60 minuteswith an infinity pull at 75 or 90 minutes In-line Filter QLA 10 μmPorous (Full Flow) Filters

TABLE B3 HPLC Instrumental Conditions Instrument A suitable gradientHPLC system equipped with an inline degasser. Column Phenomenex LunaC18(2), 50 × 4.6 mm, 3 μm PIN 00B-4251-E0 Detection UV, 220 nm ColumnTemperature 25° C. Sample Temperature Ambient Flow Rate 2.0 mL/minuteInjection Volume 10 μL Rim Time 8 minutes (See gradient table below)Mobile Phase A 0.1% TFA in HPW Mobile Phase B 0.1% TFA in ACNColumn/Needle Wash 50:50 ACN:HPW Attenuation 1000 mAUN (when applicable)Gradient Time (min), % A, % B 0.0, 95, 5 6.0, 5, 95 6.2, 95, 5 8.0, 95,5

TABLE B4 A1 (citric acid monohydrate) Dissolution Results forFospropofol Disodium Tablets, 600 mg, (% of label claim recovery) PullPoint (minutes) Vessel 5 10 15 20 25 30 40 45 60 1 10 22 31 42 48 53 6163 71 2 10 21 30 38 44 49 55 62 67 3 12 26 36 44 49 54 62 65 71 Average11 23 32 41 47 52 59 63 70 SD 1.2 2.6 3.2 3.1 2.6 2.6 3.8 1.5 2.3 % RSD10.8 11.5 9.9 7.4 5.6 5.1 6.4 2.4 3.3

TABLE B5 A2 (ascorbic acid) Dissolution Results for Fospropofol DisodiumTablets, 600 mg, (% of label claim recovery) Pull Point (minutes) Vessel5 10 15 20 25 30 40 45 60 1 26 58 76 86 89 90 93 91 92 2 31 62 78 86 9091 93 93 93 3 29 63 78 88 89 91 89 88 91 Average 29 61 77 87 89 91 92 9192 SD 2.5 2.6 1.2 1.2 0.6 0.6 2.3 2.5 1.0 % RSD 8.8 4.3 1.5 1.3 0.6 0.62.5 2.8 1.1

TABLE B6 A3 (tartaric acid) Dissolution Results for Fospropofol DisodiumTablets, 600 mg, (% of label claim recovery) Pull Point (minutes) Vessel5 10 15 20 25 30 40 45 60 1 9 20 28 33 37 41 47 50 54 2 8 18 27 33 37 4046 49 56 3 7 16 24 30 33 37 43 46 52 Average 8 18 26 32 36 39 45 48 54SD 1.0 2.0 2.1 1.7 2.3 2.1 2.1 2.1 2.0 % RSD 12.5 11.1 7.9 5.4 6.5 5.34.6 4.3 3.7

TABLE B7 A4 (malic acid) Dissolution Results for Fospropofol DisodiumTablets, 600 mg, (% of label claim recovery) Pull Point (minutes) Vessel5 10 15 20 25 30 40 45 60 1 21 48 63 70 76 77 82 82 85 2 23 48 59 66 7478 79 81 84 3 23 49 61 67 70 75 77 79 83 Average 22 48 61 68 73 77 79 8184 SD 1.2 0.6 2.0 2.1 3.1 1.5 2.5 1.5 1.0 % RSD 5.2 1.2 3.3 3.1 4.2 2.03.2 1.9 1.2

As used herein, the term “label claim” refers the total weight of thefospropofol disodium within the dosage unit.

FIG. 27 shows the dissolution profiles of the acidified tablets.

The solution pH values after the acidified tablets were dissolved in 300mL of water are shown in Table B8.

TABLE B8 pH After Acidified Tablet Dissolved in 300 mL of WaterAcidifier Excipient pH Citric Acid 3.11 Tartaric Acid 3.13 Malic Acid3.94 Ascorbic Acid 4.10

Example B2: Bioavailability Studies

The bioavailability of propofol from the fospropofol-containing dosageforms is assessed in dogs using the following general protocol.

The dogs used in the studies have the following characteristics:

-   -   Strain: Beagle    -   Condition: Purpose-bred, non-naïve    -   Source: Marshall Farms. North Rose, N.Y.    -   Number of Males: 6 (plus 1 alternate)    -   Target Age at the Initiation of Dosing: At least 8 months.    -   Target Weight at the Initiation of Dosing: 6 to 13 kg

All animals used in the studies have documentation of immunization forparvovirus, distemper, adenovirus type 2, parainfluenza, Bordetella,papilloma, and rabies.

Animals are identified with a tattoo or a subcutaneously implantedelectronic identification chip.

Each animal is inspected by a clinical veterinarian upon receipt.Animals judged to be in good health are placed immediately inacclimation for at least 10 days.

Animals judged to be suitable for testing are assigned to groupsrandomly based on body weight stratification into a block design usingcomputer program. Animals are arbitrarily reassigned to a differentgroup at the discretion of the study director based on acclimation data.

The animals are dosed as follows:

-   -   Dose Route: Tablet; Acidified Tablet    -   Frequency: Once daily; single administration        -   Method: The first day of dosing is designated as Day 1            (exception: alternate animals used for replacement after Day            1 assume the day of the animal being replaced).    -   Tablet Administration: A single dose of the test article is        administered orally via tablet.        -   Each subject receives 1 (600 mg) tablet. Doses are            irrespective of body weight.        -   In studies wherein the dogs are pretreated with pentagstrin,            the pentagastrin is administered intravenously before the            dogs are administered the fospropofol-containing tablet.

In a separate study, the dogs are orally administered a solutioncontaining 30 mg/mL fospropofol at a dose of 160 mg/kg in water ratherthan a tablet.

Bioanalytical Methods:

-   -   Venipuncture from a jugular vein (saphenous or cephalic vein is        used, if necessary).    -   Target Volume (mL): Approximately 1 mL/time point collected        without anesthesia.    -   Anticoagulant: Sodium Heparin    -   Prior to blood collection, approximately 0.05 mL of 200 mg/mL of        sodium orthovanadate (SOV) solution is added to the heparinized        blood collection tubes to prevent ex vivo conversion via        alkaline phosphatase.    -   Special Requirements: After collection, blood collection tubes        are kept on wet ice until centrifugation within 30 minutes of        collection.    -   Processing: Plasma Samples are mixed gently and centrifuged        within 30 minutes of collection. The samples are centrifuged at        2-8° C. and the resultant plasma is separated, transferred to        duplicate uniquely labeled polypropylene tubes, and kept on wet        ice until transferred to storage. Samples are stored in a        freezer set to maintain a target of −70° C.    -   Bioanalytical samples are analyzed for concentration of test        article (fospropofol) and specified metabolites (propofol) using        a validated analytical procedure.

FIG. 28 shows the propofol plasma profile comparisons of (1) 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) with no pentagastrin pretreatment; (2) 600 mg fospropofol disodiumtablet with tartaric acid acidifier (Composition A3) with nopentagastrin pretreatment; and (3) 1300 mg fospropofol disodium aqueoussolution (30 mg/mL) with no pentagastrin pretreatment.

FIG. 29 shows the propofol plasma profile comparisons of (1) 600 mgfospropofol disodium tablet with ascorbic acid acidifier (CompositionA2) with pentagastrin pretreatment; and (2) 600 mg fospropofol disodiumtablet with no acidifier (Control) with pentagastrin pretreatment.

FIG. 30 shows the propofol plasma profile comparisons of (1) 600 mgfospropofol disodium tablet with tartaric acid acidifier (CompositionA3) with no pentagastrin pretreatment; and (2) 600 mg fospropofoldisodium tablet with no acidifier (Control) with pentagastrinpretreatment.

The pharmacokinetic (PK) analysis results are shown in Table B9.

TABLE B9 PK Results AUG_(∞) Cmax (ng/mL) (ng*hr/mL) Half-life (h)(Propofol) (Propofol) (Propofol) 1300 mg Fospropofol disodium aqueoussolution (30 mg/mL) with no pentagastrin pretreatment (Propofolconcentrations in dog plasma from Fospropofol solution in Study Maledogs not pretreated with pentagastrin (from tox study, 160 mg/kg, assume8.4 kg avg weight) Mean 399.43 711.06 1.45 SD 281.70 450.13 0.58 CV 71%63% 40% 600 mg Fospropofol disodium tablet with ascorbic acid acidifier(Composition A2) with no pentagastrin pretreatment Mean 714.40 1191.91 1.48 SD 295.70 506.15 0.2  CV 41% 42% 14% 600 mg Fospropofol disodiumtablet with tartaric acid acidifier (Composition A3) with nopentagastrin pretreatment Mean 1107.50  1656.87  2.93 SD 685.43 998.423.10 CV 62% 60% 106%  600 mg Fospropofol disodium tablet with control(i.e., no acidifier) with pentagastrin pretreatment Mean 732.5  1002.22 1.34 SD 312.47 340.86 0.34 CV 43% 34% 26% 600 mg Fospropofol disodinmtablet with ascorbic acid acidifier (Composition A2) with pentagastrinpretreatment Mean 928.33 1623.93  3.84 SD 167.12 378.36 3.22 CV 18% 23%84%

The pharmacokinetic results demonstrate that administering fospropofoltogether with an acid, such as in the acidified tablets, results inincreased propofol Cmax and AUC∞ when compared to the dose adjustedexposure seen with the oral solution. See FIG. 28 ; Table B9. Thiseffect is seen using both ascorbic acid and tartaric acid as the tabletacidifiers.

In addition, the results demonstrate that administration of theacidified tablets with pentagastrin pretreatment results in increasedplasma propofol Cmax and AUC∞ compared to the plasma propofol Cmax andAUC∞ observed upon administration of a control tablet (i.e., with noacidifier) with pentagastrin pretreatment. See FIG. 29 ; Table B9.Pentagastrin pretreatment acidifies the subject's stomach contents to anacidity comparable to that of normal human stomach contents.

In addition, these results demonstrate that co-administration offospropofol disodium with tartaric acid without pentagastrinpretreatment results in increased plasma propofol Cmax and AUC∞ comparedto the plasma propofol Cmax and AUC∞ observed upon administration of acontrol tablet (i.e., with no acidifier) with pentagastrin pretreatment.See FIG. 30 ; Table B9.

The experiments described above surprisingly demonstrate that oraladministration of fospropofol together with a pharmaceuticallyacceptable acid increases the plasma propofol Cmax and AUC∞ relative tocontrols in which fospropofol is orally administered without anacidifier. Moreover, this effect is seen with multiple acids (e.g.,ascorbic acid, tartaric acid) and is seen under conditions expected inhuman subjects. Thus, the disclosed invention solves the problem ofproviding an oral dosage form that can provide useful propofolpharmacokinetics.

These results also demonstrate that co-administration of fospropofoldisodium with a pharmaceutically acceptable acid can result in decreasedvariability in Cmax and AUC∞ relative to administration without acid.

In a separate study, the food effect upon administering the compositionsof the disclosure is examined. Two groups of dogs, one fasted and onefed, are administered either the 600 mg fospropofol acidifiedcomposition comprising ascorbic acid (i.e., composition A2) or 600 mg(3×200 mg) of fospropofol control composition (i.e., HMPC capsule; noacidifier). The fasted group is fasted (no food, only water) overnightprior to being administered the fospropofol dose. The maximum individualfasting period does not exceed 24 hours. The fasted group is pretreatedwith pentagastrin. The fed group is given a high calorie meal and thedose of fospropofol is given within an hour of eating the meal. The fedgroup is not pretreated with pentagastrin.

TABLE B10 Food Effect Study Total Fospropofol (fospropofol + FospropofolPropofol propofol) Cmax AUC∞ Cmax Mean AUC_(0-∞) Composition (ng/mL)(ng*hr/mL) (ng/mL) (mol*h/mL) Ascorbic Acid 21433 18986 928 6.2779 ×10⁻⁰⁸ fasted Ascorbic Acid fed 21914 13968 573 4.4435 × 10⁻⁰⁸ Fed/Fastedratio 1.02 0.74 0.62 0.71 Control fasted 18300 15013 647 4.7778 × 10⁻⁰⁸Control fed 3131 4313 193 1.4223 × 10⁻⁰⁸ Fed/Fasted ratio 0.17 0.29 0.300.30

These results demonstrate that the acidified compositions demonstrate afood effect and that the food effect differs from that observed with thenon-acidified control composition. See FIG. 31 ; Table B10.

Both the acidified tablet and the control composition exhibit a negativefood effect on the bioavailability of fospropofol.

The extent of the food effect is modulated depending on the dosage form.

In the control compositions, the mean fospropofol Cmax (fed) is 17% ofthe mean fospropofol Cmax (fasted). In the acidified tablet, the meanfospropofol Cmax (fed) is 102% of the mean fospropofol Cmax (fasted).

In the control compositions, the mean total fospropofol Cmax (fed) is30% of the mean total fospropofol Cmax (fasted). In the acidifiedtablet, the mean total fospropofol Cmax (fed) is 71% of the mean totalfospropofol Cmax (fasted).

In the control compositions, the mean total fospropofol AUC_(0-∞)(fed)is 30% of the mean total fospropofol AUC_(0-∞)(fasted). In the acidifiedtablet, the mean total fospropofol AUC_(0-∞)(fed) is 71% of the meantotal fospropofol AUC_(0-∞)(fasted).

Example C—Fospropofol Salts Example C1

Instrumental Methods

XRPD diffractograms were collected on a Bruker D8 diffractometer usingCu Ka radiation (40 kV, 40 mA) and a 0-20 goniometer fitted with a Gemonochromator. The incident beam passes through a 2.0 mm divergence slitfollowed by a 0.2 mm anti-scatter slit and knife edge. The diffractedbeam passes through an 8.0 mm receiving slit with 2.5° Soller slitsfollowed by the Lynxeye Detector. The software used for data collectionand analysis was Diffrac Plus XRD Commander and Diffrac Plus EVArespectively.

Samples were run under ambient conditions as flat plate specimens usingpowder. The sample was prepared on a polished, zero-background (510)silicon wafer by gently pressing onto the flat surface or packed into acut cavity. The sample was rotated in its own plane. The details of thestandard Pharmorphix data collection method are:

Angular range: 2 to 420 20

Step size: 0.05° 20

Collection time: 0.5 s/step (total collection time: 6.40 min)

XRPD diffractograms were also collected on a PANalytical Empyreandiffractometer using Cu Ka radiation (45 kV, 40 mA) in transmissiongeometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with afocusing mirror were used on the incident beam. A PIXcel30 detector,placed on the diffracted beam, was fitted with a receiving slit and 0.04rad Soller slits. The software used for data collection was X'Pert DataCollector using X'Pert Operator Interface. The data were analysed andpresented using Diffrac Plus EVA or HighScore Plus.

Samples were prepared and analysed in either a metal or Millipore 96well-plate in transmission mode. X-ray transparent film was used betweenthe metal sheets on the metal well-plate and powders (approximately 1-2mg) were used. The Millipore plate was used to isolate and analysesolids from suspensions by adding a small amount of suspension directlyto the plate before filtration under a light vacuum. The scan mode forthe metal plate used the gonio scan axis, whereas a 20 scan was utilisedfor the Millipore plate. The details of the standard screening datacollection method are:

Angular range: 2.5 to 32.0° 20

Step size: 0.01300 20

Collection time: 12. 75 s/step (total collection time of 2.07 min)

Solution State NMR

¹H NMR and/or ¹³C NMR spectra were collected on a Bruker 400 MHzinstrument equipped with an auto-sampler and controlled by a DRX400console. Samples were prepared in DMSO-d6 solvent, unless otherwisestated. Automated experiments were acquired using ICON-NMR configurationwithin Topspin software, using standard Bruker-loaded experiments (¹H,¹³C {¹H}, DEPT135). Off-line analysis was performed using ACD SpectrusProcessor.

Differential Scanning Calorimetry (DSC)

DSC data were collected on a TA Instruments Q2000 equipped with a 50position auto-sampler. Typically, 0.5-3 mg of each sample, in apin-holed aluminium pan, was heated at 10° C./min from 25° C. to 300° C.A purge of dry nitrogen at 50 ml/min was maintained over the sample. Theinstrument control software was Advantage for Q Series and ThermalAdvantage and the data were analysed using Universal Analysis or TRIOS.

Thermal Gravimetric Analysis

TGA data were collected on a TA Instruments Discovery TGA, equipped witha 25 position auto-sampler. Typically, 5-10 mg of each sample was loadedonto a pre-tared aluminium DSC pan and heated at 10° C./min from ambienttemperature to 350° C. A nitrogen purge at 25 ml/min was maintained overthe sample. The instrument control software was TRIOS and the data wereanalysed using TRIOS or Universal Analysis.

Example C2

Preparation of Fospropofol

Procedure 1

Fospropofol disodium (100 mg, ±1 mg) was weighed into 3 HPLC vials anddissolved in water (5 vol. 0.5 ml) at RT. Hydrochloric acid, sulfuricacid or phosphoric acid (2.1 eq. 1 M in THF) was added to the samplesand stirred for 5 minutes and no solids were observed. Samples werecooled to 5° C. and still no solids were observed. The sample containinghydrochloric acid was selected to extract the product using DCM (3×extraction with 0.5 ml DCM). The organic layers were collected andconcentrated under rotary evaporator at 50° C. resulting in a clearcolourless oil. This oil was analysed by 1H NMR, HPLC and scanning ionchromatography.

Procedure 2

Fospropofol disodium (2.0 g) was dissolved in water (5 vol) at RT. Oncea clear solution was obtained HCl (2.1 eq., 0.5 Min water) was added anda cloudy solution was formed. The sample was transferred to a separatingfunnel and DCM (30 ml) added to extract the free acid but instead formeda thick white emulsion with no phase separation. DCM (130 ml) was addedto try and increase phase separation and water (100 ml) was added tosolubilise any NaCl precipitating out of solution. The thick whiteemulsion remained so THF was added to disrupt the emulsion, resulting inseparation of the aqueous and organic phases both cloudy solutions. Theorganic layer was collected and the aqueous layer washed with THF:DCM25:75 (2×40 ml). The organic layer was concentrated under vacuumresulting in a clear oil.

Example C3

The following procedure was used to make the potassium (from KOH),diethylamine, t-butylamine, ethylene diamine, benzathine, piperazine,ethanolamine, diethanolamine, ammonium (from NH₄H), tromethamine,benethamine, and histidine salts.

Fospropofol free acid (25 mg) was dissolved in EtOH (20 vol, 500 μl) atRT. The solutions were treated with the corresponding base (2 mol eq.,added as a stock solution) at 25° C. After 10 minutes at 25° C., themixtures were cooled to 5° C. at 0.1° C./min. After 48 hrs at 5° C.solids were filtered, air dried and analysed by XRPD, solutions wereallowed to evaporate at RT. Solids formed from evaporation were analysedby XRPD, gums and oils were placed under vacuum for 3 hours. Solids wereanalysed by XRPD and remaining gums and oils matured at 50° C./RT in 4hours temperature cycles for 48 hrs.

XRPD was again taken after 7 days storage at 40° C./75% RH. Form II ofthe diethylamine salt and Form II of the ethanolamine salt were formedby conversion of Form I of the respective salts after 7 days storage at40° C./75% RH.

Example C4

The following procedures were used to make the calcium (from CaCl₂)),magnesium (from MgCl₂), and zinc (ZnCl₂) salts.

Small Scale: Fospropofol disodium (50 mg) was dissolved in water (10vol, 500 W). The solutions were treated with the corresponding base (1mol eq., added as a stock solution). Additional ethanol (500 μl) wasadded after the formation of a thick suspension and samples stirred for1 hour before being filtered and dried in a vacuum oven for 2 hours at40° C. Form I of the calcium salt and Form I of the zinc salt wereproduced under these conditions.

Form II of the calcium salt was produced from Form I of the calcim saltafter 7 days storage at 40° C./75% RH.

Scale Up: Fospropofol disodium (500 mg) was dissolved in water (10 vol,5 ml). The solutions were treated with the corresponding base (1 mol eq.CaCl2, MgCl2, or ZnCl2). Additional ethanol* (5 ml) was added after theformation of a thick suspension and samples stirred for 1 hour beforebeing filtered and dried in a vacuum oven for 2 hours at 40° C. *ethanol(5 ml) was added three times for the sample containing the calciumcounter ion as thick precipitate continued to stop stirring. Thisprocedure produced Form III of the calcium salt and Form II of the zincsalt, ion chromatography of the product salts indicated that the calciumand magnesium salts each contained 1 eq. of the metal counterion, andthe zinc salt contained 2 eq. of the metal counterion.

Example C5

Preparation of Ethylene Diamine Salt

The free acid (500 mg) was dissolved in EtOH (20 vol, 10 ml) at 50° C.The solution was treated with ethylene diamine (2 mol eq.) at 50° C. Thesample was cooled to 5° C. at 0.1° C./min. After 48 hrs at 5° C. solidswere filtered and dried in a vacuum oven for 2 hours at 40° C.

Example C6—Intrinsic Dissolution Rate at pH 4.5

Intrinsic Dissolution Rate was measure in GI tract buff (pH-4.5 buffer):2.99 g sodium acetate trihydrate was dissolved in 14.0 ml 2N acetic acidin a 1000 ml volumetric flask, and then made to volume with deionisedwater.

Data were collected on a Sirius inform instrument fitted with a dual UVDipProbe attachment and Ag/AgCl combination pH electrode. The electrodewas calibrated using the four plus parameters derived from a blanktitration. The base titrant was standardised by titration with TRIS. 0.5M HCl and NaOH aqueous solutions were used as the acid and base titrantsrespectively for the testing. Stirring was facilitated by a dualoverhead stirrer to allow thorough mixing within the vessel, and mediawas introduced via a capillary bundle attached to a dispensing bankcomprised of six precision dispensing units. A Peltier heating jacketwas used to maintain the temperature of the titration vessel. Discs wereintroduced to the vessel via the tablet picker housed in the probe arm,after the desired temperature of the media had been reached. Siriusinform Assay Design, Control and Refine software were used to design,run and refine data respectively.

The reference sample was prepared as a 20.1 mM stock solution in water.One MEC data sets were then collected using five additions each of thewater stock using 250, 500 and three times 750 μI aliquots,respectively. UV Spectra were then collected after each addition of thewater stock to build a multi-point MEC calibration, using a 20 mm pathlength probe. The MEC data set was then imported into the dissolutiondata files in order to convert the UV absorbance measured toconcentration. The concentration range for UV data collected was 124.8μM-1.4 mM. MEC data were collected at 37° C. to match the dissolutionexperiments. Same MEC data was used as for faSSGf IDR experiments due tothere being no change in the UV profile at this pH.

Intrinsic Dissolution Rate (IDR):

Approximately. 10-20 mg of the sample was compressed in a 3 mm discrecess, under 100 kg for 2 minutes, with greaseproof paper on thecompression base, to form nondisintegrating discs. The discs were thenplugged with a bung so that only one surface was exposed to the mediaduring analysis and transferred to the Sirius inform dissolutionapparatus. Analysis was performed at 37° C. in 36 ml water and 4 ml GImedia with the pH set to 4.5, for 1 hour with UV spectra collected every10 seconds. A stir speed of 100 rpm was used with a 20 mm path lengthprobe. The IDR was calculated based on the surface area of the 3 mm discrecess used (7.07 mm2 surface area). XRPD analysis was performed on allsamples, both after compression of the material into the disc recess,and post dissolution analysis to observe any change in form. Allanalysis was performed using XRPD 2.

X-Ray Powder Diffraction (XRPD2):

XRPD diffractograms were collected on a Bruker AXS C2 GADDSdiffractometer using Cu Ka radiation (40 kV, 40 mA), an automated XYZstage, a laser video microscope for auto sample positioning and aVantec-500 2-dimensional area detector. X-ray optics consists of asingle Gobel multilayer mirror coupled with a pinhole collimator of 0.3mm. The beam divergence, i.e. the effective size of the X-ray beam onthe sample, was approximately 4 mm. A 9-9 continuous scan mode wasemployed with a sample—detector distance of 20 cm which gives aneffective 29 range of 1.5°-32.5°. The sample was exposed to the X-raybeam for 120 seconds under ambient conditions. The software used fordata collection and analysis was GADDS for Win7/XP and Diffrac Plus EVArespectively.

The results are shown in the Table C1 below.

TABLE C1 Average IDR (mg/min/cm²) XRPD Analysis Salt pH DuplicateAverage Post Dissolution Sodium 4.6 38.04, 35.67 37 Not PerformedEthylene 4.5 0.76, 0.78 0.77 Amorphous Diamine (Example 5) Calcium 4.50.51, 0.37 0.44 Amorphous (Example 4) Magnesium 4.5 0.47, 0.44 0.46Amorphous (Example 4) Zinc 4.5 0.19, 0.18 0.18 Amorphous (Example 4)

Example C7—Intrinsic Dissolution Rate at pH 1.9

Intrinsic Dissolution Rate was Determined in Simulated Intestinal Fluidat pH Base Buffer (FaSSGF):

Sodium chloride (2.0 g) and deionized water added to a 1000 mlvolumetric flask, pH adjusted to 1.6 with concentrated hydrochloricFaSSGF acid, made up to volume with deionised water.

FaSSGF Media:

Phares SIF (simulated intestinal fluid) powder (0.06 g) was added to a 1L volumetric flask and made to volume with base buffer.

Data were collected on a Sirius inform instrument fitted with a dual UVDip Probe attachment and Ag/AgCl combination pH electrode. The electrodewas calibrated using the four plus parameters derived from a blanktitration. The base titrant was standardised by titration with TRIS. 0.5M HCl and NaOH aqueous solutions were used as the acid and base titrantsrespectively for the testing. Stirring was facilitated by a dualoverhead stirrer to allow thorough mixing within the vessel, and mediawas introduced via a capillary bundle attached to a dispensing bankcomprised of six precision dispensing units. A Peltier heating jacketwas used to maintain the temperature of the titration vessel. Discs wereintroduced to the vessel via the tablet picker housed in the probe arm,after the desired temperature of the media had been reached. Siriusinform Assay Design, Control and Refine software were used to design,run and refine data respectively.

Molar Extinction Coefficient (MEC):

The reference sample was prepared as a 20.1 mM stock solution in water.One MEC data sets were then collected using five additions each of thewater stock using 250, 500 and three times 750 μI aliquots,respectively. UV Spectra were then collected after each addition of thewater stock to build a multi-point MEC calibration, using a 20 mm pathlength probe. The MEC data set was then imported into the dissolutiondata files in order to convert the UV absorbance measured toconcentration. The concentration range for UV data collected was 124.8μM-1.4 mM. MEC data were collected in the dissolution media {faSSGf) andat 37° C. to match the dissolution experiments.

Intrinsic Dissolution Rate (IDR):

Ca. 10-20 mg of the sample was compressed in a 3 mm disc recess, under100 kg for 2 minutes, with greaseproof paper on the compression base, toform nondisintegrating discs. The discs were then plugged with a bung sothat only one surface was exposed to the media during analysis andtransferred to the Sirius inform dissolution apparatus. Analysis wasperformed at 37° C. in 40 ml faSSGf media for 1 hour with UV spectracollected every 30 seconds. A stir speed of 100 rpm was used with a 20mm path length probe. The IDR was calculated based on the surface areaof the 3 mm disc recess used (7.07 mm2 surface area). XRPD analysis wasperformed on all samples, both after compression of the material intothe disc recess, and post dissolution analysis to observe any change inform. All analysis was performed using XRPD 2.

X-Ray Powder Diffraction (XRPD2):

XRPD diffractograms were collected on a Bruker AXS C2 GADDSdiffractometer using Cu Ka radiation (40 kV, 40 mA), an automated XYZstage, a laser video microscope for auto sample positioning and aVantec-500 2-dimensional area detector. X-ray optics consists of asingle Gobel multilayer mirror coupled with a pinhole collimator of 0.3mm. The beam divergence, i.e. the effective size of the X-ray beam onthe sample, was approximately 4 mm. A 9-9 continuous scan mode wasemployed with a sample—detector distance of 20 cm which gives aneffective 29 range of 1.5°-32.5°. The sample was exposed to the X-raybeam for 120 seconds under ambient conditions. The software used fordata collection and analysis was GADDS for Win7/XP and Diffrac Plus EVArespectively.

The results are shown in the Table below.

Average IDR (mg/min/cm²) XRPD Analysis Salt pH Duplicate Average PostDissolution Sodium 1.8 41.5, 44.2 43 Not Performed Ethylene 1.6 1.16,1.29 1.2 Amorphous Diamine (Example 5) Calcium 1.8 1.15, 1.14 1.2Amorphous (Example 4) Magnesium 1.8 1.51, 1.67 1.6 Amorphous (Example 4)Zinc 1.8 1.22, 1.31 1.3 Amorphous (Example 4)

Example C8

A fospropofol calcium salt tablet within a tablet can be prepared asfollows. The core tablet contains fospropofol calcium salt (200 mg; 20%by wt. dosage form), microcrystalline cellulose (100 mg; 10% by wt. ofdosage form), pregelatinized starch (e.g., Starch 1500)(97.5 mg; 9.75%by weight of dosage form), magnesium stearate (2.5 mg; 0.25% by wt. ofdosage form). The outer layer, which surrounds the core tablet, containsfospropofol calcium salt (400 mg; 40% by wt. of dosage form),microcrystalline cellulose (100 mg; 10% wt. of dosage form),pregelatinized starch (e.g., Starch 1500)(97.5 mg; 9.75% by wt. ofdosage form), magnesium stearate (2.5 mg; 0.25% by wt. of dosage form).This is a modified-release dosage form. The outer layer dissolvesrapidly in the stomach. The core tablet dissolves slowly in the stomach,and further dissolves in the intestines.

Example C9

A fospropofol magnesium salt bilayer tablet can be prepared as follows.

One layer contains fospropofol magnesium salt (200 mg; 20% by wt. ofbilayer tablet), microcrystalline cellulose (100 mg; 10% by wt. ofbilayer tablet), pregelatinized starch (e.g., Starch 1500)(97.5 mg;9.75% by wt. of bilayer tablet), magnesium stearate (2.5 mg; 0.25% bywt. of bilayer tablet).

The other layer contains fospropofol magnesium salt (400 mg; 40% by wt.of bilayer tablet), microcrystalline cellulose (100 mg; 10% by wt. ofbilayer tablet.), pregelatinized starch (e.g., Starch 1500)(97.5 mg;9.75% by wt. of bilayer tablet), magnesium stearate (2.5 mg; 0.25% bywt. of bilayer tablet).

This is a modified-release dosage form. One layer dissolves rapidly inthe stomach. The other layer dissolves slowly in the stomach, andfurther dissolves in the intestines.

Example C10

A Fospropofol Dosage form with immediate release and delayed releasecomponents can be prepared as follows.

The delayed release component contains fospropofol zinc salt (200 mg;20% by wt. of final dosage form), microcrystalline cellulose (100 mg;10% by wt. of final dosage form), pregelatinized starch (e.g., Starch1500)(17.5 mg; 1.75% by wt. of final dosage form), HMPC (80 mg; 8% bywt. of final dosage form), magnesium stearate (2.5 mg; 0.25% by wt. offinal dosage form).

The immediate release component contains fospropofol zinc salt (400 mg;40% by wt. of final dosage form), microcrystalline cellulose (100 mg;10% by wt. of final dosage form), pregelatinized starch (e.g., Starch1500)(97.5 mg; 9.75% by wt. of final dosage form), and magnesiumstearate (2.5 mg; 0.25% by wt. of final dosage form).

This is a modified-release dosage form. The delayed release componentgranules and the immediate release component granules may be combinedand pressed into a tablet, or may be combined in a capsule.

Example C11

A Fospropofol Dosage form with immediate release and enteric coatedcomponents can be prepared as follows.

The enteric coated component contains fospropofol ethylene diamine salt(200 mg; 20% by wt. of final dosage form), microcrystalline cellulose(100 mg; 10% by wt. of final dosage form), pregelatinized starch (e.g.,Starch 1500)(47.5 mg; 4.75% by wt. of final dosage form), magnesiumstearate (2.5 mg; 0.25% by wt. of final dosage form), Eudragit L (50 mg;5% by wt. of final dosage form).

The immediate release component contains fospropofol ethylene diamine(400 mg; 40% by wt. of final dosage form), microcrystalline cellulose(100 mg; 10% by wt. of final dosage form), pregelatinized starch (e.g.,Starch 1500)(97.5 mg; 9.75% by wt. of final dosage form), and magnesiumstearate (2.5 mg; 0.25% by wt. of final dosage form).

This is a modified-release dosage form. The enteric coated componentgranules and the immediate release component granules or beads may becombined and pressed into a tablet, or may be combined in a capsule.

Example C12

Randomized, double blind, parallel group, comparative evaluation of thesafety-tolerability, pharmacokinetics, and efficacy of 3 dosage forms ofPO fospropofol salt administered to young healthy male and femalevolunteers for the acute treatment of moderate or severe migraineheadache is conducted as follows.

This study will assess the safety-tolerability, pharmacokinetics, andefficacy (pain relief), in a similar population as in Example C1, of asingle administration of one of three dosage forms (the dosage forms ofExamples C8, C9, and C10).

The study will also assess the efficacy for relief of associatedsymptoms (nausea, photophobia, phonophobia) of a single administrationof one of three dosage forms (the dosage forms of Examples C8, C9, andC10).

Inclusion criteria: Male and female volunteers, age 18-65 yearsinclusive with an established diagnosis of migraine, with or withoutaura, according to IHS criteria. The age at the time of initial migrainediagnosis <50 yo, and the time since initial diagnisis of migraine >oneyear. The estimated frequency of migraine episodes classified asmoderate or severe is at least one per month on average over the pastyear. Subjects with coexisting headache other than migraine are eligibleprovided that these headaches are distinguishable from the subject'smigraine headaches. No relevant contraindication to use of fospropofolor propofol according to FDA approved labeling. Concomitant medicationsintended to reduce the frequency of migraine are permitted provided thatthe dose is stable for at least 3 months prior to enrolment andestimated headache frequency meets the criterion above. If concomitantmedications intended to reduce the frequency of migraine arediscontinued prior to the study, these medications must be discontinuedat least one month prior to enrolment. Patients will also have anabsence of any clinically significant medical condition that, in theopinion of the investigator or the Sponsor, may be potentiallyassociated with an increased risk from participation in the study.

Exclusion criteria: Subjects with any medical condition (e.g., sleepapnea) which, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from the administration ofstudy drug. Subjects with a contraindication to use of fospropofol orpropofol according to FDA approved labeling. Subjects with any medicalcondition, which, in the opinion of the investigator or the Sponsor, maybe potentially associated with an increased risk from participation inthe study. Subjects who require concomitant medications, the use ofwhich, in the opinion of the investigator or the Sponsor, may bepotentially associated with an increased risk from participation in thestudy. Subjects unable or unwilling to provide informed consent. Womenof childbearing potential must be on adequate, reliable contraception.

A separate cohort of 36 subjects will be randomized to receive one of 3regimens (N=12/group) under double-blind conditions, each regimencomprising a single administration of one of the dosage forms of ExampleC8, C9, or C10. Double-blinding will be preserved by administering anappropriate number of active and placebo capsules for the second dose.

The subject's blood will be sampled pre-dose (within 15 min of dosing)and post-dose: 5, 10, 20, 30, 45, 90 minutes and 2, 4, 6, and 9 hourspost-dose. Plasma samples will be assayed for fospropofol and propofolusing validated analytical method(s) according to the principles of GoodLaboratory Practice.

The following parameters will be calculated with fospropofol andpropofol plasma concentrations: AUC0-30 min, AUC0-2h, AUC0-t, AUC0-inf,Cmax, Residual area, Tmax, T_(1/2 el), Kel, Cl/F, Vd/F, and Vd/F/kg.

Subject's will assess headache pain utilizing a 4-point Likert Scale tobe assessed at baseline (within 15 min of dosing), and post-dose at 15min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h (in clinic) andfollowing discharge (by diary) at 24 h and 48 h post-dosing. Subjectswill be asked to record by patient diary any recurrence or worsening ofheadache pain, and time of onset or worsening. (Note that a qualifyingheadache must be of at least moderate severity.)

Subjects will assess presence/absence of the most bothersome associatedsymptom for the presenting headache at baseline (within 15 min ofdosing), and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8h, 10 h (in clinic) and following discharge (by diary) at 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subject's will assess the presence/absence of nausea/vomiting,photophobia, and/or phonophobia at baseline (within 15 min of dosing),and post-dose at 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h(in clinic) and following discharge (by diary) at 12 h, 24 h and 48 hpost-dosing. Subjects will be asked to record by patient diary anyrecurrence or worsening of the most bothersome symptom, and time ofonset or worsening.

Subjects will be instructed to report any adverse events directly to theinvestigators or clinic staff. Subjects will be instructed to record inthe patient diary any adverse events emerging following discharge. Allsubjects will have telephone access to the investigator or investigatorstaff to report any urgent concerns in the course of the study.

In order to detect the possible emergence of any clinically significantcardiac arrhythmia or other abnormality cardiac telemetry will bemonitored from pre-dose until 10 hours post-dose. Volunteers with anyclinically significant ECG abnormality at baseline (pre-dose) will beexcluded.

Blood pressure (BP), heart rate (HR), respiratory rate (RR), and pulseoximetry will be recorded within 15 min pre-dose and at approximately 30min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing.

Modified Observer's Assessment of Alertness/Sedation (OAA/S) scorewithin 15 min pre-dose and at approximately 15 min, 30 min, and 1, 1.5,2, 2.5, 3, 4, 5, 6, 8, and 10 hours after dosing will be assessed.

Hematology, biochemistry, and urinalysis will be assessed at screeningand end of study participation.

Alcohol breath test, urine cotinine determination, and urine drug screenwill be assessed at check-in.

A physical examination will be conducted at screening and end of study.An abbreviated physical exam will be conducted at clinic check-in.

Subjects will be monitored throughout the study by clinic staff foradverse events. A physician will be on site for each drug administrationand until 10 hours post-dose, and available on call for the remainder ofthe study.

This study will demonstrate that each of the dosage forms of ExamplesC8, C9, or C10, is safe and effective in treating migraine.

The disclosure is also directed to the following aspects:

-   -   Aspect 1. Method of Treating Migraine Aspects A method of        treating migraine in a patient in need thereof, comprising        administering to said patient an effective amount of        fospropofol, a pharmaceutically acceptable salt of fospropofol,        or mixtures thereof, in one or more doses.    -   Aspect 2. The method of aspect 1, wherein said effective amount        of fospropofol, a pharmaceutically acceptable salt of        fospropofol, or mixtures thereof, is administered orally,        perorally, subcutaneously, intramuscularly, intravenously,        transmucosally, sublingually, buccally, transdermally,        intraintestinally, rectally, or intrapulmonarily.    -   Aspect 3. The method of aspect 2, wherein said effective amount        of fospropofol, a pharmaceutically acceptable salt of        fospropofol, or mixtures thereof, is administered perorally.    -   Aspect 4. The method of aspect 1, wherein said pharmaceutically        acceptable salt of fospropofol is fospropofol disodium.    -   Aspect 5. The method of aspect 1, wherein said effective amount        of fospropofol, a pharmaceutically acceptable salt of        fospropofol, or mixtures thereof, is 100-4800 mg (on a        fospropofol basis).    -   Aspect 6. The method of aspect 5, wherein said effective amount        is 100-3600 mg (on a fospropofol basis).    -   Aspect 7. The method of aspect 1, wherein said effective amount        of fospropofol, a pharmaceutically acceptable salt of        fospropofol, or mixtures thereof, is administered in one dose.    -   Aspect 8. The method of aspect 1, wherein said effective amount        of fospropofol, a pharmaceutically acceptable salt of        fospropofol, or mixtures thereof, is administered in more than        one dose.    -   Aspect 9. The method of aspect 8, wherein the time interval        between administration of the first dose and administration of        the second dose is about 5-120 minutes.    -   Aspect 10. The method of aspect 8, wherein the first dose        provides 10-100% (by weight on a fospropofol basis) of the        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof.    -   Aspect 11. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma Cmax or mean Cmax of propofol of at least        200-1600 ng/mL.    -   Aspect 12. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma Cmax or mean Cmax of propofol of no greater        than 5000 ng/mL.    -   Aspect 13. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofol of        no greater than 3200 ng hr/mL.    -   Aspect 14. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma mean AUC_(20min)/mean AUC_(60min) ratio on a        mean concentration vs. time curve that is less than 0.29.    -   Aspect 15. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma mean AUC_(20min)/mean AUC_(120min) ratio on        a mean concentration vs. time curve that is less than 0.23.    -   Aspect 16. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma mean AUC_(30min)/mean AUC_(60min) ratio on a        mean concentration vs. time curve that is less than 0.68.    -   Aspect 17. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma mean AUC_(30min)/mean AUC_(120min) ratio on        a mean concentration vs. time curve that is less than 0.55.    -   Aspect 18. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a mean C₂₀/mean C₆₀ ratio is less than 5.    -   Aspect 19. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a mean C₂₀/mean C₁₂₀ ratio is less than 76.    -   Aspect 20. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a mean C₃₀/mean C₆₀ ratio is less than 2.4.    -   Aspect 21. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a mean C₃₀/mean C₁₂₀ ratio is less than 36.    -   Aspect 22. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma AUC_(2hr) or mean AUC_(2hr) of propofol no        greater than 40-80% of AUC_(0-∞) or mean AUC_(0-∞).    -   Aspect 23. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma concentration or mean concentration of        propofol of 100-1600 ng/mL for at least 30 minutes.    -   Aspect 24. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a plasma concentration or mean concentration of        propofol at a time point 0.5-6 hr after Tmax or median Tmax that        is 50-90% of plasma Cmax or mean Cmax of propofol.    -   Aspect 25. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a Tmax of 0.1 hr-2 hour.    -   Aspect 26. The method of aspect 1, wherein said administering an        effective amount of fospropofol, a pharmaceutically acceptable        salt of fospropofol, or mixtures thereof, in one or more doses,        results in a reduction of the patient's migraine pain.    -   Aspect 27. The method of aspect 1, wherein said administering to        the patient an effective amount of fospropofol, a        pharmaceutically acceptable salt of fospropofol, or mixtures        thereof, in one or more doses, results in no clinically        meaningful risk of developing unresponsiveness to vigorous        tactile or painful stimulation as assessed by the Modified        Observer's Assessment of Alertness (OAA/S) Scale.    -   Aspect 28. A pharmaceutical composition comprising fospropofol,        a pharmaceutically acceptable salt of fospropofol, or mixtures        thereof, and a pharmaceutically acceptable excipient.    -   Aspect 29. The pharmaceutical composition of aspect 28, wherein        the pharmaceutical composition is a solid.    -   Aspect 30. The pharmaceutical composition of aspect 28, wherein        the pharmaceutical composition is a capsule (gelatin or        non-gelatin), enteric capsule, cachet, tablet, beads, or powder.    -   Aspect 31. The pharmaceutical composition of aspect 28,        comprising fospropofol, a pharmaceutically acceptable salt of        fospropofol, or mixtures thereof, in an amount of 100-4800 mg        (on a fospropofol basis).    -   Aspect 32. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a plasma Cmax or mean Cmax of propofol of at least 200-1600        ng/mL.    -   Aspect 33. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a plasma Cmax or mean Cmax of propofol of no greater than 5000        ng/mL.    -   Aspect 34. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a plasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater        than 3200 ng hr/mL.    -   Aspect 35. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a plasma AUC_(2hr) or mean AUC_(2hr) of propofol no greater than        40-80% of AUC_(0-∞) or mean AUC_(0-∞).    -   Aspect 36. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a plasma concentration or mean concentration of propofol of        100-1600 ng/mL for at least 30 minutes.    -   Aspect 37. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a mean C₂₀/mean C₆₀ ratio is less than 5.    -   Aspect 38. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a mean C₂₀/mean C₁₂₀ ratio is less than 76.    -   Aspect 39. The pharmaceutical composition of aspect 28, that        when administered to a patient in one or more doses, results in        a plasma concentration or mean concentration of propofol at a        time point 0.5-6 hr after Tmax or median Tmax that is 50-90% of        plasma C_(max) or mean C_(max) of propofol.

Propofol Prodrug Aspects:

-   -   Aspect 1. A method of treating migraine in a patient in need        thereof, comprising administering to said patient an effective        amount of a propofol prodrug, a pharmaceutically acceptable salt        of a propofol prodrug, or mixtures thereof, in one or more        doses.    -   Aspect 2. The method of aspect 1, wherein said effective amount        of a propofol prodrug, a pharmaceutically acceptable salt of a        propofol prodrug, or mixtures thereof, is administered orally,        perorally, subcutaneously, intramuscularly, intravenously,        transmucosally, sublingually, buccally, transdermally,        intraintestinally, rectally, or intrapulmonarily.    -   Aspect 3. The method of aspect 2, wherein said effective amount        of a propofol prodrug, a pharmaceutically acceptable salt of a        propofol prodrug, or mixtures thereof, is administered        perorally.    -   Aspect 4. The method of aspect 1, wherein said effective amount        of a propofol prodrug, a pharmaceutically acceptable salt of a        propofol prodrug, or mixtures thereof, is 100-4800 mg (on a        propofol prodrug basis or on a propofol basis).    -   Aspect 5. The method of aspect 4, wherein said effective amount        is 100-3600 mg (on a propofol prodrug basis or on a propofol        basis).    -   Aspect 6. The method of aspect 1, wherein said effective amount        of a propofol prodrug, a pharmaceutically acceptable salt of a        propofol prodrug, or mixtures thereof, is administered in one        dose.    -   Aspect 7. The method of aspect 1, wherein said effective amount        of a propofol prodrug, a pharmaceutically acceptable salt of a        propofol prodrug, or mixtures thereof, is administered more than        one dose.    -   Aspect 8. The method of aspect 7, wherein the time interval        between administration of the first dose and administration of        the second dose is about 5-120 minutes.    -   Aspect 9. The method of aspect 8, wherein the first dose        provides 10-100% (by weight on a propofol prodrug basis) of the        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof.    -   Aspect 10. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma Cmax or mean Cmax of        propofol of at least 200-1600 ng/mL.    -   Aspect 11. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma Cmax or mean Cmax of        propofol of no greater than 5000 ng/mL.    -   Aspect 12. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma AUC_(2hr) or mean        AUC_(2hr) of propofol of no greater than 3200 ng hr/mL.    -   Aspect 13. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma mean AUC_(20min)/mean        AUC_(60min) ratio on a mean concentration vs. time curve that is        less than 0.29.    -   Aspect 14. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma mean AUC_(20min)/mean        AUC_(120min) ratio on a mean concentration vs. time curve that        is less than 0.23.    -   Aspect 15. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma mean AUC_(30min)/mean        AUC_(60min) ratio on a mean concentration vs. time curve that is        less than 0.68.    -   Aspect 16. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma mean AUC_(30min)/mean        AUC_(120min) ratio on a mean concentration vs. time curve that        is less than 0.55.    -   Aspect 17. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a mean C₂₀/mean C₆₀ ratio is less        than 5.    -   Aspect 18. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a mean C₂₀/mean C₁₂₀ ratio is less        than 76.    -   Aspect 19. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a mean C₃₀/mean C₆₀ ratio is less        than 2.4.    -   Aspect 20. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a mean C₃₀/mean C₁₂₀ ratio is less        than 36.    -   Aspect 21. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma AUC_(2hr) or mean        AUC_(2hr) of propofol no greater than 40-80% of AUC_(0-∞) or        mean AUC_(0-∞).    -   Aspect 22. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma concentration or mean        concentration of propofol of 100-1600 ng/mL for at least 30        minutes.    -   Aspect 23. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a plasma concentration or mean        concentration of propofol at a time point 0.5-6 hr after Tmax or        median Tmax that is 50-90% of plasma Cmax or mean Cmax of        propofol.    -   Aspect 24. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a Tmax of 0.1 hr-2 hour.    -   Aspect 25. The method of aspect 1, wherein said administering an        effective amount of a propofol prodrug, a pharmaceutically        acceptable salt of a propofol prodrug, or mixtures thereof, in        one or more doses, results in a reduction of the patient's        migraine pain.    -   Aspect 26. The method of aspect 1, wherein said administering to        the patient an effective amount of a propofol prodrug, a        pharmaceutically acceptable salt of a propofol prodrug, or        mixtures thereof, in one or more doses, results in no clinically        meaningful risk of developing unresponsiveness to vigorous        tactile or painful stimulation as assessed by the Modified        Observer's Assessment of Alertness (OAA/S) Scale.    -   Aspect 27. A pharmaceutical composition comprising a propofol        prodrug, a pharmaceutically acceptable salt of a propofol        prodrug, or mixtures thereof, and a pharmaceutically acceptable        excipient.    -   Aspect 28. The pharmaceutical composition of aspect 27, wherein        the pharmaceutical composition is a solid.    -   Aspect 29. The pharmaceutical composition of aspect 27, wherein        the pharmaceutical composition is a capsule (gelatin or        non-gelatin), enteric capsule, cachet, tablet, beads, or powder.    -   Aspect 30. The pharmaceutical composition of aspect 27,        comprising a propofol prodrug, a pharmaceutically acceptable        salt of a propofol prodrug, or mixtures thereof, in an amount of        100-4800 mg (on a propofol prodrug basis or on a propofol        basis).    -   Aspect 31. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a plasma Cmax or mean Cmax of propofol of at least 200-1600        ng/mL.    -   Aspect 32. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a plasma Cmax or mean Cmax of propofol of no greater than 5000        ng/mL.    -   Aspect 33. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a plasma AUC_(2hr) or mean AUC_(2hr) of propofol of no greater        than 3200 ng hr/mL.    -   Aspect 34. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a plasma AUC_(2hr) or mean AUC_(2hr) of propofol no greater than        40-80% of AUC_(0-∞) or mean AUC_(0-∞).    -   Aspect 35. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a plasma concentration or mean concentration of propofol of        100-1600 ng/mL for at least 30 minutes.    -   Aspect 36. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a mean C₂₀/mean C₆₀ ratio is less than 5.    -   Aspect 37. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a mean C₂₀/mean C₁₂₀ ratio is less than 76.    -   Aspect 38. The pharmaceutical composition of aspect 27, that        when administered to a patient in one or more doses, results in        a plasma concentration or mean concentration of propofol at a        time point 0.5-6 hr after Tmax or median Tmax that is 50-90% of        plasma Cmax or mean Cmax of propofol.

Fospropofol Salt Aspects

-   -   Aspect 1. A pharmaceutically acceptable salt of fospropofol,        wherein said salt is a potassium, diethylamine, t-butylamine,        ethylene diamine, benzathine, piperazine, ethanolamine,        diethanolamine, ammonium, tromethamine, benethamine, histidine,        calcium, magnesium, or zinc salt.    -   Aspect 2. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is a potassium salt.    -   Aspect 3. The potassium salt of aspect 2, wherein said salt is        characterized by an X-ray powder diffraction pattern        substantially as shown in FIG. 34 .    -   Aspect 4. The potassium salt of aspect 2 or aspect 3, wherein        said salt is characterized by an X-ray powder diffraction        pattern comprising peaks at 12.3, 17.3, and 20.9 degrees±0.2        degrees 2-theta, on the 2-theta scale with lambda=1.54 angstroms        (Cu Kα).    -   Aspect 5. The potassium salt of any one of aspects 2-4, wherein        said salt is characterized by an X-ray powder diffraction        pattern comprising peaks at three or more of 12.3, 15.5, 16.2,        16.4, 17.3, 18.0, 18.7, 19.5, 20.0, 20.9, 23.1, 28.1, and 28.7        degrees±0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 6. The potassium salt of any one of aspects 2-5, wherein        said salt is characterized by a differential scanning        calorimetry (DSC) thermogram substantially as shown in FIG. 35        when heated at a rate of 10° C./min.    -   Aspect 7. The potassium salt of any one of aspects 2-6, wherein        said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 62° C., about 144° C., or about 262° C. when heated at a        rate of 10° C./min.    -   Aspect 8. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is a diethylamine salt.    -   Aspect 9. The diethylamine salt of aspect 8, wherein said salt        is the Form II salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 36 .    -   Aspect 10. The diethylamine salt of either aspect 8 or aspect 9,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 5.8 and 11.0 degrees±0.2        degrees 2-theta, on the 2-theta scale with lambda=1.54 angstroms        (Cu Kα).    -   Aspect 11. The diethylamine salt of any one of aspects 8-10,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at two or more of 5.8,        11.0, 11.5, 14.6, 17.6, 22.0, 23.0, and 24.1 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 12. The diethylamine salt of aspect 8, wherein said salt        is the Form I salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 37 .    -   Aspect 13. The diethylamine salt of either aspect 8 or aspect        12, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 10.9 and 11.4 degrees t        0.2 degrees 2-theta, on the 2-theta scale with lambda=1.54        angstroms (Cu Kα).    -   Aspect 14. The diethylamine salt of any one of aspects 8, 12, or        13, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at two or more of 10.9,        11.4, 14.6, 24.2, 25.9, and 27.5 degrees±0.2 degrees 2-theta, on        the 2-theta scale with lambda=1.54 angstroms (Cu Kα).    -   Aspect 15. The diethylamine salt of any one of aspects 8, or        12-14, wherein said salt is characterized by a differential        scanning calorimetry (DSC) thermogram substantially as shown in        FIG. 38 when heated at a rate of 10° C./min.    -   Aspect 16. The diethylamine salt of any one of aspects 8, or        12-15, wherein said salt is characterized by a differential        scanning calorimetry (DSC) thermogram comprising an endothermic        peak at about 98° C. when heated at a rate of 10° C./min.    -   Aspect 17. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the t-butylamine        salt.    -   Aspect 18. The t-butylamine salt of aspect 17, wherein said salt        is characterized by an X-ray powder diffraction pattern        substantially as shown in FIG. 40 .    -   Aspect 19. The t-butylamine salt of either aspect 17 or aspect        18, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peak at 12.2 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 20. The t-butylamine salt of any one of aspects 17-19,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 9.0,        9.6, 12.2, 17.1, 19.5, 21.3, 21.7, 23.9, 26.4, 28.3, and 28.8        degrees±0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 21. The t-butylamine salt of any one of aspects 17-20,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram substantially as shown in FIG. 41        when heated at a rate of 10° C./min.    -   Aspect 22. The t-butylamine salt of any one of aspects 17-21,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 58° C., or at about 195° C. when heated at a rate of 10°        C./min.    -   Aspect 23. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the ethylene diamine        salt.    -   Aspect 24. The ethylene diamine salt of aspect 23, wherein said        salt is characterized by an X-ray powder diffraction pattern        substantially as shown in FIG. 43 .    -   Aspect 25. The ethylene diamine salt of either aspect 23 or        aspect 24, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peak at 12.6 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 26. The ethylene diamine salt of any one of aspects        23-25, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 11.9,        12.6, 13.7, 15.1, 17.8, 20.1, 23.6, and 23.9 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 27. The ethylene diamine salt of any one of aspects        23-26, wherein said salt is characterized by a differential        scanning calorimetry (DSC) thermogram substantially as shown in        FIG. 44 when heated at a rate of 10° C./min.    -   Aspect 28. The ethylene diamine salt of any one of aspects        23-27, wherein said salt is characterized by a differential        scanning calorimetry (DSC) thermogram comprising an endothermic        peak at about 89° C. or at about 192° C. when heated at a rate        of 10° C./min.    -   Aspect 29. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the benzathine salt.    -   Aspect 30. The benzathine salt of aspect 29, wherein said salt        is characterized by a differential scanning calorimetry (DSC)        thermogram substantially as shown in FIG. 46 when heated at a        rate of 10° C./min.    -   Aspect 31. The benzathine salt of either aspect 29 or aspect 30,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 111° C. when heated at a rate of 10° C./min.    -   Aspect 32. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the piperazine salt.    -   Aspect 33. The piperazine salt of aspect 32, wherein said salt        is characterized by an x-ray powder diffraction pattern        substantially as shown in FIG. 48 .    -   Aspect 34. The piperazine salt of either aspect 32 or aspect 33,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 4.9, 9.2, and 10.9        degrees t 0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 35. The piperazine salt of any one of aspects 32-34,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 4.9,        9.2, 10.9, 13.0, 16.3, 17.4, 20.0, 20.4, 21.3, 21.9, 23.2, and        24.3 degrees±0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 36. The piperazine salt of any one of aspects 32-35,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram substantially as shown in FIG. 49        when heated at a rate of 10° C./min.    -   Aspect 37. The piperazine salt of any one of aspects 32-36,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 96° C., about 151° C., or about 195° C. when heated at a        rate of 10° C./min.    -   Aspect 38. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the ethanolamine        salt.    -   Aspect 39. The ethanolamine salt of aspect 38, wherein said salt        is the Form II salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 51 .    -   Aspect 40. The ethanolamine salt of either aspect 38 or aspect        39, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 12.5, and 14.2        degrees±0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 41. The ethanolamine salt of any one of aspects 38-40,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at two or more of 4.8,        12.5, 14.2, 21.9, and 25.1 degrees±0.2 degrees 2-theta, on the        2-theta scale with lambda=1.54 angstroms (Cu Kα).    -   Aspect 42. The ethanolamine salt of aspect 38, wherein said salt        is the Form I salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 52 .    -   Aspect 43. The ethanolamine salt of either aspect 38 or aspect        42, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peak at 10.0 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 44. The ethanolamine salt of any one of aspects 38, 42,        or 43, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at two or more of 10.0,        15.3, 15.9, 17.0, 18.5, 19.6, and 20.9 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 45. The ethanolamine salt of any one of aspects 38, or        42-44, wherein said salt is characterized by a differential        scanning calorimetry (DSC) thermogram substantially as shown in        FIG. 53 when heated at a rate of 10° C./min.    -   Aspect 46. The ethanolamine salt of any one of aspects 38, or        42-45, wherein said salt is characterized by a differential        scanning calorimetry (DSC) thermogram comprising an endothermic        peak at about 96° C., or about 174° C. when heated at a rate of        10° C./min.    -   Aspect 47. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the diethanolamine        salt.    -   Aspect 48. The diethanolamine salt of aspect 47, wherein said        salt is characterized by a differential scanning calorimetry        (DSC) thermogram substantially as shown in FIG. 55 when heated        at a rate of 10° C./min.    -   Aspect 49. The diethanolamine salt of either aspect 47 or aspect        48, wherein said salt is characterized by a differential        scanning calorimetry (DSC) thermogram comprising an endothermic        peak at about 57° C. when heated at a rate of 10° C./min.    -   Aspect 50. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the ammonium salt.    -   Aspect 51. The ammonium salt of aspect 50, wherein said salt is        characterized by an x-ray powder diffraction pattern        substantially as shown in FIG. 57 .    -   Aspect 52. The ammonium salt of either aspect 50 or aspect 51,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peak at 18.1 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 53. The ammonium salt of any one of aspects 50-52,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 12.2,        14.2, 15.9, 18.1, 18.5, 19.2, 21.1, 21.8, and 25.8 degrees±0.2        degrees 2-theta, on the 2-theta scale with lambda=1.54 angstroms        (Cu Kα).    -   Aspect 54. The ammonium salt of any one of aspects 50-53,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram substantially as shown in FIG. 58        when heated at a rate of 10° C./min.    -   Aspect 55. The ammonium salt of any one of aspects 50-54,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 76° C. when heated at a rate of 10° C./min.    -   Aspect 56. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the tromethamine        salt.    -   Aspect 57. The tromethamine salt of aspect 56, wherein said salt        is characterized by an x-ray powder diffraction pattern        substantially as shown in FIG. 59 .    -   Aspect 58. The tromethamine salt of either aspect 56 or aspect        57, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 10.0, 16.6, and 17.3        degrees 0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 59. The tromethamine salt of any one of aspects 56-58,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 6.0,        10.0, 10.7, 16.6, 17.3, 18.3, 24.7, and 25.2 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 60. The tromethamine salt of any one of aspects 56-59,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram substantially as shown in FIG. 60        when heated at a rate of 10° C./min.    -   Aspect 61. The tromethamine salt of any one of aspects 56-60,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 103° C., about 133° C., or about 171° C. when heated at a        rate of 10° C./min.    -   Aspect 62. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the benethamine        salt.    -   Aspect 63. The benethamine salt of aspect 62, wherein said salt        is characterized by an x-ray powder diffraction pattern        substantially as shown in FIG. 62 .    -   Aspect 64. The benethamine salt of either aspect 62 or aspect        63, wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peak at 16.4 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 65. The benethamine salt of any one of aspects 62-64,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 5.5,        7.2, 8.5, 11.7, 12.6, 16.4, 17.7, and 19.6 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 66. The benethamine salt of any one of aspects 62-65,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram substantially as shown in FIG. 63        when heated at a rate of 10° C./min.    -   Aspect 67. The benethamine salt of any one of aspects 62-66,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 86° C. when heated at a rate of 10° C./min.    -   Aspect 68. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the histidine salt.    -   Aspect 69. The histidine salt of aspect 68, wherein said salt is        characterized by an X-ray powder diffraction pattern        substantially as shown in FIG. 65 .    -   Aspect 70. The histidine salt of either aspect 68 or aspect 69,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 11.2, 15.3, and 18.9        degrees±0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 71. The histidine salt of any one of aspects 68-70,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 11.2,        15.3, 18.9, 21.1, 21.5, 24.2, and 30.2 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 72. The histidine salt of any one of aspects 68-71,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram substantially as shown in FIG. 66        when heated at a rate of 10° C./min.    -   Aspect 73. The histidine salt of any one of aspects 68-72,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 196° C. or at about 202° C. when heated at a rate of 10°        C./min.    -   Aspect 74. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the calcium salt.    -   Aspect 75. The calcium salt of aspect 74, wherein said salt is        the Form I salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 68 .    -   Aspect 76. The calcium salt of either aspect 74 or aspect 75,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising a peak at 4.7 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 77. The calcium salt of any one of aspects 74-76, wherein        said salt is characterized by a DSC thermogram substantially as        shown in FIG. 69 , or by a TGA profile substantially as shown in        FIG. 69 .    -   Aspect 78. The calcium salt of aspect 74, wherein said salt is        the Form II salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 70 .    -   Aspect 79. The calcium salt of either aspect 74 or aspect 78,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 5.1, 7.0, 7.7, 8.6, 9.2,        and 14.4 degrees±0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 80. The calcium salt of any one of aspects 74, 78, or 79,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 4.3,        4.5, 5.0, 5.1, 7.0, 7.7, 8.6, 9.2, and 14.4 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 81. The calcium salt of aspect 74, wherein said salt is        the Form III salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 71 .    -   Aspect 82. The calcium salt of either aspect 74 or aspect 81,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 4.8, and 9.7 degrees±0.2        degrees 2-theta, on the 2-theta scale with lambda=1.54 angstroms        (Cu Kα).    -   Aspect 83. The calcium salt of any one of aspects 74, 81, or 82,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 4.8,        9.7, 11.6, 11.9, 14.5, 17.2, and 29.1 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 84. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the magnesium salt.    -   Aspect 85. The magnesium salt of aspect 84, wherein said salt is        characterized by an X-ray powder diffraction pattern        substantially as shown in FIG. 72 .    -   Aspect 86. The magnesium salt of either aspect 84 or aspect 85,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising a peak at 4.5 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 87. The magnesium salt of any one of aspects 84-86,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at two or more of 4.5, 9.1,        13.6, 20.8, and 27.9 degrees±0.2 degrees 2-theta, on the 2-theta        scale with lambda=1.54 angstroms (Cu Kα).    -   Aspect 88. The magnesium salt of any one of aspects 84-87,        wherein said salt is characterized by a DSC thermogram        substantially as shown in FIG. 40 , or by a TGA profile        substantially as shown in FIG. 73 .    -   Aspect 89. The magnesium salt of any one of aspects 84-88,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 129° C. when heated at a rate of 10° C./min.    -   Aspect 90. The pharmaceutically acceptable salt of fospropofol        according to aspect 1, wherein said salt is the zinc salt.    -   Aspect 91. The zinc salt of aspect 90, wherein said salt is the        Form II salt characterized by an X-ray powder diffraction        pattern substantially as shown in FIG. 74 .    -   Aspect 92. The zinc salt of either aspect 90 or aspect 91,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising a peak at 4.9 degrees±0.2 degrees        2-theta, on the 2-theta scale with lambda=1.54 angstroms (Cu        Kα).    -   Aspect 93. The zinc salt of aspect 90, wherein said salt is the        Form I salt characterized by an X-ray powder diffraction pattern        substantially as shown in FIG. 75 .    -   Aspect 94. The zinc salt of either aspect 90 or aspect 93,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at 8.1, 9.6, and 10.3        degrees±0.2 degrees 2-theta, on the 2-theta scale with        lambda=1.54 angstroms (Cu Kα).    -   Aspect 95. The zinc salt of any one of aspects 90, 93, or 94,        wherein said salt is characterized by an X-ray powder        diffraction pattern comprising peaks at three or more of 5.1,        8.1, 9.6, 10.3, 11.6, 12.2, 18.2, 18.6, and 26.3 degrees±0.2        degrees 2-theta, on the 2-theta scale with lambda=1.54 angstroms        (Cu Kα).    -   Aspect 96. The zinc salt of any one of aspects 90, or 93-95,        wherein said salt is characterized by a DSC thermogram        substantially as shown in FIG. 76 , or by a TGA profile        substantially as shown in FIG. 76 .    -   Aspect 97. The zinc salt of any one of aspects 90, or 93-96,        wherein said salt is characterized by a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        about 114° C. or about 210° C. when heated at a rate of 10°        C./min.    -   Aspect 98. A pharmaceutical composition comprising the        fospropofol salt according to any one of aspects 1-97, and a        pharmaceutically acceptable excipient.    -   Aspect 99. A method of treating migraine in a patient in need        thereof, comprising administering to said patient an effective        amount of the fospropofol salt according to any one of aspects        1-97.    -   Aspect 100. The method of aspect 99 wherein said patient's        migraine is refractory migraine.    -   Aspect 101. The method of any one of claims 99 or 100, wherein        said effective amount of fospropofol salt is administered        orally, perorally, subcutaneously, intramuscularly,        intravenously, transmucosally, sublingually, buccally,        transdermally, intraintestinally, rectally, or intrapulmonarily.

Acidified Pharmaceutical Dosage Forms

-   -   Aspect 1. A pharmaceutical dosage form for oral administration        comprising fospropofol or a pharmaceutically acceptable salt        thereof, a pharmaceutically acceptable acid.    -   Aspect 2. The pharmaceutical dosage form according to aspect 1        comprising fospropofol.    -   Aspect 3. The pharmaceutical dosage form according to aspect 1        comprising a pharmaceutically acceptable salt of fospropofol.    -   Aspect 4. The pharmaceutical dosage form according to aspect 3,        wherein the pharmaceutically acceptable salt of fospropofol is        fospropofol disodium.    -   Aspect 5. The pharmaceutical dosage form according to any one of        the preceding aspects, wherein the pharmaceutically acceptable        acid is on the FDA inactive ingredient database (IID) for        approved drug products or generally recognized as safe (GRAS).    -   Aspect 6. The pharmaceutical dosage form according to any one of        the preceding aspects, wherein the pharmaceutically acceptable        acid is 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,        2-hydroxethanesulfonic acid, 4-acetamidobenzoic acid,        4-aminosalicyclic acid, acetic acid, aceturic acid, Acid        hydrolyzed proteins, Acid Modified Starch, Aconitic Acid, adipic        acid, alginic acid, a-oxo-glutaric acid, benzenesulfonic acid,        benzoic acid, butyric acid, camphor-10-sulfonic acid, camphoric        acid, capric acid, caproic acid, caprylic acid, carbonic acid,        Cholic acid, cinnamic acid, citric acid, cyclamic acid,        D(−)-Lactic acid, Desoxycholic acid, D-glucaric acid,        D-glucoheptonic acid, D-glucuronic acid,        Di(tert-butyl)naphthalenedisulfonic acid,        Di(tert-butyl)naphthalenesulfonic acid, DL-lactic acid,        DL-mandelic acid, DL-tartaric acid, tartaric acid,        dodecylsulfuric acid, Erythorbic acid (D-isoascorbic acid),        ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid,        fumaric acid, galactaric acid, gentisic acid, glutaric acid,        glycerophosphoric acid, Glycocholic acid, glycolic acid,        hexanedioic acid, hippuric acid, hydrobromic acid, Hydrochloric        acid, Iron naphthenate, iron salts, iron salts, isobutyric acid,        L(+)-lactic acid, L(+)-potassium acid tartrate, L(+)-tartaric        acid, Lactic acid, lactobionic acid, L-ascorbic acid, ascorbic        acid, L-aspartic acid, lauric acid, L-glutamic acid, L-Glutamic        acid hydrochloride. Linoleic acid, L-Malic acid, L-pyroglutamic        acid, L-tartaric acid, maleic acid, malic acid, malonic acid,        methanesulfonic acid, monobasic potassium phosphate, monobasic        sodium phosphate, naphthalene-1,5-disulfonic acid,        naphthalene-2-sulfonic acid, naphthenic acids, Niacin (nicotinic        acid), nicotinic acid, nitric acid, octanoic acid, oleic acid,        orotic acid, oxalic acid, palmitic acid, pamoic acid, Pectin low        acid, Pectinic acid, phosphoric acid, propanoic acid, Propionic        acid, p-toluenesulfonic acid, pyruvic acid, saccharin, salicylic        acid, sebacic acid, Sodium acid pyrophosphate, Sodium aluminum        phosphate, sodium metabisulfite, Sorbic acid, stearic acid,        succinic acid, sulfuric acid, tall oil fatty acids, Tannic acid        (hydrolyzable gallotannins), Taurocholic acid, thiocyanic acid,        Thiodipropionic acid, trifluoroacetic acid, undec-10-enoic acid,        orange juice, apple juice, grapefruit juice, or a combination        thereof or a combination thereof.    -   Aspect 7. The pharmaceutical dosage form according to any one of        the preceding aspects, wherein the pharmaceutically acceptable        acid is ascorbic acid, citric acid, malic acid, or tartaric        acid.    -   Aspect 8. The pharmaceutical dosage form according to any one of        the preceding aspects, wherein the pharmaceutically acceptable        acid is ascorbic acid.    -   Aspect 9. The pharmaceutical dosage form according to any one of        the preceding aspects, wherein the pharmaceutically acceptable        acid is tartaric acid.    -   Aspect 10. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein the pharmaceutically        acceptable acid is citric acid.    -   Aspect 11. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein the pharmaceutically        acceptable acid is malic acid.    -   Aspect 12. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of water at 25° C. results in a solution having a pH of        6.3 or less.    -   Aspect 13. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of water at 25° C. results in a solution having a pH of        4.5 or less.    -   Aspect 14. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of water at 25° C. results in a solution having a pH of        4.2 or less.    -   Aspect 15. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of water at 25° C. results in a solution having a pH of        4.0 or less.    -   Aspect 16. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of 0.1 N HCl at 37° C., results in at least 30% of the        fospropofol or pharmaceutically acceptable salt thereof (on a        fospropofol basis) in the dosage form being released from the        dosage form within 60 minutes.    -   Aspect 17. The pharmaceutical dosage form according to aspect        16, wherein dissolution of an amount of the dosage form        containing a therapeutically effective amount of fospropofol, or        a pharmaceutically acceptable salt thereof, in 300 mL of 0.1 N        HCl at 37° C. results in at least 30% of the fospropofol or        pharmaceutically acceptable salt thereof (on a fospropofol        basis) in the dosage form being released from the dosage form        within 30 minutes.    -   Aspect 18. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of 0.1 N HCl at 37° C. results in at least 50% of the        fospropofol or pharmaceutically acceptable salt thereof (on a        fospropofol basis) in the dosage form being released from the        dosage form within 60 minutes.    -   Aspect 19. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of 0.1 N HCl at 37° C. results in at least 50% of the        fospropofol or pharmaceutically acceptable salt thereof (on a        fospropofol basis) in the dosage form being released from the        dosage form within 30 minutes.    -   Aspect 20. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of 0.1 N HCl at 37° C. results in at least 90% of the        fospropofol or pharmaceutically acceptable salt thereof (on a        fospropofol basis) in the dosage form being released from the        dosage form within 30 minutes.    -   Aspect 21. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of 0.1 N HCl at 37° C. results in at least 90% of the        fospropofol or pharmaceutically acceptable salt thereof (on a        fospropofol basis) in the dosage form being released from the        dosage form within 60 minutes.    -   Aspect 22. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein dissolution of an amount of        the dosage form containing a therapeutically effective amount of        fospropofol, or a pharmaceutically acceptable salt thereof, in        300 mL of 0.1 N HCl at 37° C. results in release of at least 90%        of the fospropofol from the dosage form within 30 minutes.    -   Aspect 23. The pharmaceutical dosage form according to any one        of the preceding aspects, wherein the mole ratio of fospropofol        or a pharmaceutically acceptable salt thereof (on a fospropofol        basis) to pharmaceutically acceptable acid is 3:1 or less.    -   Aspect 24. A method of administering fospropofol or a        pharmaceutically acceptable salt thereof to a subject in need        thereof, comprising orally administering to said subject a        pharmaceutical dosage form according to any one of the preceding        aspects.    -   Aspect 25. A method of administering fospropofol or a        pharmaceutically acceptable salt thereof to a subject in need        thereof, said method comprising orally administering        fospropofol, or a pharmaceutically acceptable salt thereof, and        a pharmaceutically acceptable acid, to the subject.    -   Aspect 26. The method of aspect 24 or aspect 25, wherein said        fospropofol, or a pharmaceutically acceptable salt thereof, and        said pharmaceutically acceptable acid are present in the same        unit dosage form.    -   Aspect 27. The method of aspect 25, wherein all or a portion of        said pharmaceutically acceptable acid is administered separately        from the unit dosage form comprising said fospropofol, or a        pharmaceutically acceptable salt thereof.    -   Aspect 28. The method according to any one of aspects 24 to 27,        wherein said pharmaceutically acceptable acid is ascorbic acid,        citric acid, malic acid, tartaric acid, succinic acid, fumaric        acid, maleic acid, lactic acid, monobasic sodium phosphate,        monobasic potassium phosphate, sodium metabisulfite, apple        juice, orange juice, or grapefruit juice.    -   Aspect 29. The method according to aspect 28, wherein said        pharmaceutically acceptable acid is ascorbic acid, citric acid,        malic acid, or tartaric acid.    -   Aspect 30. The method according to aspect 29, wherein said        pharmaceutically acceptable acid is ascorbic acid.    -   Aspect 31. The method according to aspect 29, wherein said        pharmaceutically acceptable acid is citric acid.    -   Aspect 32. The method according to aspect 29, wherein said        pharmaceutically acceptable acid is malic acid.    -   Aspect 33. The method according to aspect 29, wherein said        pharmaceutically acceptable acid is tartaric acid.    -   Aspect 34. The method of any one of aspects 24 to 33, wherein        said subject is experiencing hypochlorhydria or achlorhydria        prior to the administration.    -   Aspect 35. The method according to aspect 34, wherein said        subject has been administered a proton pump inhibitor (PPI)        prior to the administration.    -   Aspect 36. The method of any one of aspects 24 to 35, wherein        said administration results in a propofol Cmax that is greater        than a propofol Cmax resulting from administering fospropofol,        or a pharmaceutically acceptable salt thereof, without        administration of the pharmaceutically acceptable acid.    -   Aspect 37. The method of aspect 36, wherein the propofol Cmax is        at least 1.5 times greater than a propofol Cmax resulting from        administering fospropofol, or a pharmaceutically acceptable salt        thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 38. The method of aspect 36, wherein the propofol C_(max)        is at least 2 times greater than a propofol C_(max) resulting        from administering fospropofol, or a pharmaceutically acceptable        salt thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 39. The method of aspect 36, wherein the propofol Cmax is        at least 2.5 times greater than a propofol Cmax resulting from        administering fospropofol, or a pharmaceutically acceptable salt        thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 40. The method of aspect 36, wherein the propofol Cmax is        at least 3 times greater than a propofol Cmax resulting from        administering fospropofol, or a pharmaceutically acceptable salt        thereof without administration of the pharmaceutically        acceptable acid.    -   Aspect 41. The method of any one of aspects 24 to 40, wherein        said administration results in a propofol AUC_(∞) that is        greater than a propofol AUC_(∞) resulting from administering        fospropofol, or a pharmaceutically acceptable salt thereof,        without administration of the pharmaceutically acceptable acid.    -   Aspect 42. The method of aspect 41, wherein the propofol AUC_(∞)        is at least 1.5 times greater than a propofol AUC_(∞) resulting        from administering fospropofol, or a pharmaceutically acceptable        salt thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 43. The method of aspect 41, wherein the propofol AUC_(∞)        is at least 2 times greater than a propofol AUC_(∞) resulting        from administering fospropofol, or a pharmaceutically acceptable        salt thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 44. The method of aspect 41, wherein the propofol AUC_(∞)        is at least 2.5 times greater than a propofol AUC_(∞) resulting        from administering fospropofol, or a pharmaceutically acceptable        salt thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 45. The method of aspect 41, wherein the propofol AUC_(∞)        is at least 3 times greater than a propofol AUC_(∞) resulting        from administering fospropofol, or a pharmaceutically acceptable        salt thereof, without co-administration of the pharmaceutically        acceptable acid.    -   Aspect 46. The method of any one of aspects 24 to 45, wherein        said method is directed to treating a disease or disorder in a        subject in need thereof.    -   Aspect 47. The method of aspect 46, wherein said method        comprises orally administering to a subject the pharmaceutical        dosage form of any one of aspects 1 to 23.    -   Aspect 48. The method of aspect 46, comprising orally        administering fospropofol, or a pharmaceutically acceptable salt        thereof, and a pharmaceutically acceptable acid, to a subject.    -   Aspect 49. The method of any one of aspects 46 to 48, wherein        the disease or disorder is migraine, acute repetitive seizures,        seizure clusters, neuropathic pain, postherpetic neuralgia,        traumatic brain injury, Alzheimer's disease, epilepsy, anxiety,        fragile X syndrome, post-traumatic stress disorder, lysosomal        storage disorders (Niemann-Pick type C disease), depression        (including post-partum depression), premenstrual dysphoric        disorder, alcohol craving, or smoking cessation.    -   Aspect 50. The method of aspect 49, wherein the disease or        disorder is migraine.

Methods of using Acidified Pharmaceutical Dosage Forms

-   -   Aspect 1. A method of treating a disease or disorder in subject        in need thereof, said method comprising orally administering to        said subject a pharmaceutical dosage form comprising        fospropofol, or a pharmaceutically acceptable salt thereof, and        a pharmaceutically acceptable acid, wherein the administration        results in a plasma fospropofol Cmax (fed) that is at least 30%        of the corresponding plasma fospropofol Cmax (fasted).    -   Aspect 2. The method according to aspect 1, wherein the        administration results in a plasma fospropofol C_(max) (fed)        that is at least 90% of the corresponding plasma fospropofol        C_(max) (fasted).    -   Aspect 3. The method according to aspect 1, wherein the        pharmaceutically acceptable acid is ascorbic acid, citric acid,        malic acid, or tartaric acid.    -   Aspect 4. The method according to aspect 1, wherein the        pharmaceutically acceptable acid is ascorbic acid.    -   Aspect 5. The method according to aspect 1, wherein the        pharmaceutically acceptable acid is tartaric acid.    -   Aspect 6. The method according to aspect 1, wherein the        pharmaceutically acceptable acid is citric acid.    -   Aspect 7. The method according to aspect 1, wherein the        pharmaceutically acceptable acid is malic acid.    -   Aspect 8. The method according to aspect 1, wherein said subject        is a human.    -   Aspect 9. The method of aspect 1, wherein the disease or        disorder is migraine, acute repetitive seizures, seizure        clusters, neuropathic pain, postherpetic neuralgia, traumatic        brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X        syndrome, post-traumatic stress disorder, lysosomal storage        disorders (Niemann-Pick type C disease), depression (including        post-partum depression), premenstrual dysphoric disorder,        alcohol craving, smoking cessation, tremor, essential tremor,        Parkinsonian tremor, orthostatic tremor, primary writing tremor,        cerebellar tremor, rubral tremor, neuropathic tremor, or        dystonic tremor.    -   Aspect 10. The method of aspect 1, wherein the disease or        disorder is migraine.    -   Aspect 11. A method of treating a disease or disorder in subject        in need thereof, said method comprising orally administering to        said subject a pharmaceutical dosage form comprising        fospropofol, or a pharmaceutically acceptable salt thereof, and        a pharmaceutically acceptable acid, wherein the administration        results in a plasma total fospropofol AUC_(∞) (fed) that is at        least 40% of the corresponding plasma total fospropofol AUC_(∞)        (fasted).    -   Aspect 12. The method according to aspect 11, wherein the        administration results in a plasma total fospropofol AUC_(∞)        (fed) that is at least 70% of the corresponding plasma total        fospropofol AUC_(∞) (fasted).    -   Aspect 13. The method according to aspect 11, wherein the        pharmaceutically acceptable acid is ascorbic acid, citric acid,        malic acid, or tartaric acid.    -   Aspect 14. The method according to aspect 11, wherein the        pharmaceutically acceptable acid is ascorbic acid.    -   Aspect 15. The method according to aspect 11, wherein the        pharmaceutically acceptable acid is tartaric acid.    -   Aspect 16. The method according to aspect 11, wherein the        pharmaceutically acceptable acid is citric acid.    -   Aspect 17. The method according to aspect 11, wherein the        pharmaceutically acceptable acid is malic acid.    -   Aspect 18. The method according to aspect 11, wherein said        subject is a human.    -   Aspect 19. The method of aspect 11, wherein the disease or        disorder is migraine, acute repetitive seizures, seizure        clusters, neuropathic pain, postherpetic neuralgia, traumatic        brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X        syndrome, post-traumatic stress disorder, lysosomal storage        disorders (Niemann-Pick type C disease), depression (including        post-partum depression), premenstrual dysphoric disorder,        alcohol craving, smoking cessation, tremor, essential tremor,        Parkinsonian tremor, orthostatic tremor, primary writing tremor,        cerebellar tremor, rubral tremor, neuropathic tremor, or        dystonic tremor.    -   Aspect 20. The method of aspect 11, wherein the disease or        disorder is migraine.

Acidified Composition Aspects

-   -   Aspect 1. A method of treating a disease or disorder in subject        in need thereof, said method comprising orally administering to        said subject a pharmaceutical dosage form comprising fospropofol        disodium, and a pharmaceutically acceptable acid that is        ascorbic acid, citric acid, malic acid, fumaric acid, or        tartaric acid, wherein the mole ratio of fospropofol disodium to        the pharmaceutically acceptable acid is 3:1 or less.    -   Aspect 2. The method according to aspect 1, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is ascorbic acid.    -   Aspect 3. The method according to aspect 1, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is tartaric acid.    -   Aspect 4. The method according to aspect 1, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is citric acid.    -   Aspect 5. The method according to aspect 1, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is malic acid.    -   Aspect 6. The method according to aspect 1, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is fumaric acid.    -   Aspect 7. The method according to aspect 1, wherein said subject        is a human.    -   Aspect 8. The method of aspect 1, wherein the disease or        disorder is migraine, acute repetitive seizures, seizure        clusters, neuropathic pain, postherpetic neuralgia, traumatic        brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X        syndrome, post-traumatic stress disorder, lysosomal storage        disorders (Niemann-Pick type C disease), depression (including        post-partum depression), premenstrual dysphoric disorder,        alcohol craving, or smoking cessation.    -   Aspect 9. The method of aspect 8, wherein the disease or        disorder is migraine.    -   Aspect 10. The method of aspect 1, wherein said subject has or        is suspected of having hypochlorhydria or achlorhydria prior to        the administration of the pharmaceutical dosage form.    -   Aspect 11. The method according to aspect 10, wherein said        subject has been administered a proton pump inhibitor (PPI)        prior to the administration of the pharmaceutical dosage form.    -   Aspect 12. The method of aspect 1, wherein said administration        of the pharmaceutical dosage form results in a propofol Cmax        that is greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of a        pharmaceutically acceptable acid.    -   Aspect 13. The method of aspect 12, wherein the propofol Cmax is        at least 1.2 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 14. The method of aspect 13, wherein the propofol Cmax is        at least 3 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 15. The method of aspect 1, wherein said administration        of the pharmaceutical dosage form results in a propofol AUC_(∞)        that is greater than a propofol AUC_(∞) resulting from        administering fospropofol disodium without administration of a        pharmaceutically acceptable acid.    -   Aspect 16. The method of aspect 15, wherein the propofol AUC_(∞)        is at least 1.5 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.    -   Aspect 17. The method of aspect 16, wherein the propofol AUC_(∞)        is at least 3 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.    -   Aspect 18. A method of treating a disease or disorder in subject        in need thereof, said method comprising orally administering to        said subject a pharmaceutical dosage form comprising fospropofol        disodium, and a pharmaceutically acceptable acid that is        ascorbic acid, citric acid, malic acid, fumaric acid, or        tartaric acid, wherein dissolution of an amount of the dosage        form containing 10-4800 mg (on a fospropofol basis) of        fospropofol disodium, in 300 mL of water at 25° C., results in a        solution having a pH of 4.5 or less.    -   Aspect 19. The method according to aspect 18, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is ascorbic acid.    -   Aspect 20. The method according to aspect 18, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is tartaric acid.    -   Aspect 21. The method according to aspect 18, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is citric acid.    -   Aspect 22. The method according to aspect 18, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is malic acid.    -   Aspect 23. The method according to aspect 18, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is fumaric acid.    -   Aspect 24. The method according to aspect 18, wherein said        subject is a human.    -   Aspect 25. The method of aspect 18, wherein the disease or        disorder is migraine, acute repetitive seizures, seizure        clusters, neuropathic pain, postherpetic neuralgia, traumatic        brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X        syndrome, post-traumatic stress disorder, lysosomal storage        disorders (Niemann-Pick type C disease), depression (including        post-partum depression), premenstrual dysphoric disorder,        alcohol craving, or smoking cessation.    -   Aspect 26. The method of aspect 18, wherein the disease or        disorder is migraine.    -   Aspect 27. The method of aspect 18, wherein said subject has or        is suspected of having hypochlorhydria or achlorhydria prior to        the administration of the pharmaceutical dosage form.    -   Aspect 28. The method according to aspect 27, wherein said        subject has been administered a proton pump inhibitor (PPI)        prior to the administration of the pharmaceutical dosage form.    -   Aspect 29. The method of aspect 18, wherein said administration        of the pharmaceutical dosage form results in a propofol Cmax        that is greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of a        pharmaceutically acceptable acid.    -   Aspect 30. The method of aspect 29, wherein the propofol Cmax is        at least 1.2 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 31. The method of aspect 30, wherein the propofol Cmax is        at least 3 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 32. The method of aspect 18, wherein said administration        of the pharmaceutical dosage form results in a propofol AUC_(∞)        that is greater than a propofol AUC_(∞) resulting from        administering fospropofol disodium without administration of a        pharmaceutically acceptable acid.    -   Aspect 33. The method of aspect 32, wherein the propofol AUC_(∞)        is at least 1.5 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.    -   Aspect 34. The method of aspect 33, wherein the propofol AUC_(∞)        is at least 3 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.    -   Aspect 35. A method of treating a disease or disorder in subject        in need thereof, said method comprising orally administering to        said subject a pharmaceutical dosage form comprising fospropofol        disodium, and a pharmaceutically acceptable acid that is        ascorbic acid, citric acid, malic acid, fumaric acid, or        tartaric acid, wherein dissolution of an amount of the dosage        form containing 10-4800 mg (on a fospropofol basis) of        fospropofol disodium, in 300 mL of 0.1 N HCl at 37° C., results        in release of at least 30% of the fospropofol from the dosage        form within 30 minutes.    -   Aspect 36. The method according to aspect 35, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is ascorbic acid.    -   Aspect 37. The method according to aspect 35, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is tartaric acid.    -   Aspect 38. The method according to aspect 35, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is citric acid.    -   Aspect 39. The method according to aspect 35, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is malic acid.    -   Aspect 40. The method according to aspect 35, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form is fumaric acid.    -   Aspect 41. The method according to aspect 35, wherein said        subject is a human.    -   Aspect 42. The method of aspect 35, wherein the disease or        disorder is migraine, acute repetitive seizures, seizure        clusters, neuropathic pain, postherpetic neuralgia, traumatic        brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X        syndrome, post-traumatic stress disorder, lysosomal storage        disorders (Niemann-Pick type C disease), depression (including        post-partum depression), premenstrual dysphoric disorder,        alcohol craving, or smoking cessation.    -   Aspect 43. The method of aspect 42, wherein the disease or        disorder is migraine.    -   Aspect 44. The method of aspect 35, wherein said subject has or        is suspected of having hypochlorhydria or achlorhydria prior to        the administration of the pharmaceutical dosage form.    -   Aspect 45. The method according to aspect 44, wherein said        subject has been administered a proton pump inhibitor (PPI)        prior to the administration of the pharmaceutical dosage form.    -   Aspect 46. The method of aspect 35, wherein said administration        of the pharmaceutical dosage form results in a propofol Cmax        that is greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of a        pharmaceutically acceptable acid.    -   Aspect 47. The method of aspect 46, wherein the propofol Cmax is        at least 1.2 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 48. The method of aspect 47, wherein the propofol Cmax is        at least 3 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 49. The method of aspect 35, wherein said administration        of the pharmaceutical dosage form results in a propofol AUC_(∞)        that is greater than a propofol AUC_(∞) resulting from        administering fospropofol disodium without administration of a        pharmaceutically acceptable acid.    -   Aspect 50. The method of aspect 49, wherein the propofol AUC_(∞)        is at least 1.5 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.    -   Aspect 51. The method of aspect 50, wherein the propofol AUC_(∞)        is at least 3 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.

Acidified Dosage Form Aspects

-   -   Aspect 1. A pharmaceutical dosage form for oral administration        comprising fospropofol, or a pharmaceutically acceptable salt        thereof, and a pharmaceutically acceptable acid wherein the mole        ratio of fospropofol, or a pharmaceutically acceptable salt        thereof, to the pharmaceutically acceptable acid is 3:1 or less.    -   Aspect 2. 2. The pharmaceutical dosage form according to aspect        1, wherein said pharmaceutical dosage form comprises        fospropofol.    -   Aspect 3. 3. The pharmaceutical dosage form according to aspect        1, wherein said pharmaceutical dosage form comprises a        pharmaceutically acceptable salt of fospropofol.    -   Aspect 4. 4. The pharmaceutical dosage form according to aspect        3, wherein said pharmaceutically acceptable salt of fospropofol        is fospropofol disodium.    -   Aspect 5. 5. The pharmaceutical dosage form according to aspect        1, in the form of a tablet, capsule, or softgel.    -   Aspect 6. 6. The pharmaceutical dosage form according to aspect        1, wherein the mole ratio of fospropofol, or a pharmaceutically        acceptable salt thereof, to the pharmaceutically acceptable acid        is 2:1 or less.    -   Aspect 7. 7. The pharmaceutical dosage form according to aspect        1, wherein the mole ratio of fospropofol, or a pharmaceutically        acceptable salt thereof, to the pharmaceutically acceptable acid        is 1.5:1 or less.    -   Aspect 8. A method of treating a disease or disorder in subject        in need thereof, said method comprising orally administering to        said subject pharmaceutical dosage form according to aspect 1.    -   Aspect 9. The method according to aspect 8, wherein said subject        is a human.    -   Aspect 10. The method of aspect 8, wherein the disease or        disorder is migraine, acute repetitive seizures, seizure        clusters, neuropathic pain, postherpetic neuralgia, traumatic        brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X        syndrome, post-traumatic stress disorder, lysosomal storage        disorders (Niemann-Pick type C disease), depression (including        post-partum depression), premenstrual dysphoric disorder,        alcohol craving, or smoking cessation.    -   Aspect 11. The method of aspect 10, wherein the disease or        disorder is migraine.    -   Aspect 12. The method of aspect 8, wherein said subject has or        is suspected of having hypochlorhydria or achlorhydria prior to        the administration of the pharmaceutical dosage form.    -   Aspect 13. The method according to aspect 12, wherein said        subject has been administered a proton pump inhibitor (PPI)        prior to the administration of the pharmaceutical dosage form.    -   Aspect 14. The method of aspect 8, wherein said administration        of the pharmaceutical dosage form results in a propofol Cmax        that is greater than a propofol Cmax resulting from        administering fospropofol, or a pharmaceutically acceptable salt        thereof, without administration of a pharmaceutically acceptable        acid.    -   Aspect 15. The method of aspect 14, wherein the propofol Cmax is        at least 1.2 times greater than a propofol Cmax resulting from        administering fospropofol, or a pharmaceutically acceptable salt        thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 16. The method of aspect 15, wherein the propofol Cmax is        at least 3 times greater than a propofol Cmax resulting from        administering fospropofol, or a pharmaceutically acceptable salt        thereof, without administration of the pharmaceutically        acceptable acid.    -   Aspect 17. The method of aspect 8, wherein said administration        of the pharmaceutical dosage form results in a propofol AUC_(∞)        that is greater than a propofol AUC_(∞) resulting from        administering fospropofol, or a pharmaceutically acceptable salt        thereof, without administration of a pharmaceutically acceptable        acid.    -   Aspect 18. The method of aspect 17, wherein the propofol AUC_(∞)        is at least 1.5 times greater than a propofol AUC_(∞) resulting        from administering fospropofol, or a pharmaceutically acceptable        salt thereof, without administration of a pharmaceutically        acceptable acid.    -   Aspect 19. The method of aspect 18, wherein the propofol AUC_(∞)        is at least 3 times greater than a propofol AUC_(∞) resulting        from administering fospropofol, or a pharmaceutically acceptable        salt thereof, without administration of a pharmaceutically        acceptable acid.

Acidified Composition Aspects II

-   -   Aspect 1. A pharmaceutical dosage form for oral administration        comprising fospropofol disodium, and a pharmaceutically        acceptable acid that is ascorbic acid, citric acid, malic acid,        or tartaric acid.    -   Aspect 2. The pharmaceutical dosage form according to aspect 1,        wherein the pharmaceutically acceptable acid is ascorbic acid.    -   Aspect 3. The pharmaceutical dosage form according to aspect 1,        wherein the pharmaceutically acceptable acid is tartaric acid.    -   Aspect 4. The pharmaceutical dosage form according to aspect 1,        wherein the pharmaceutically acceptable acid is citric acid.    -   Aspect 5. The pharmaceutical dosage form according to aspect 1,        wherein the pharmaceutically acceptable acid is malic acid.    -   Aspect 6. The pharmaceutical dosage form according to aspect 1,        in the form of a tablet, capsule, or softgel.    -   Aspect 7. The pharmaceutical dosage form according to aspect 1,        wherein dissolution of an amount of the dosage form containing a        therapeutically effective amount of fospropofol, or a        pharmaceutically acceptable salt thereof, in 300 mL of water at        25° C., results in a solution having a pH of 4.5 or less.    -   Aspect 8. The pharmaceutical dosage form according to aspect 1,        wherein dissolution of an amount of the dosage form containing a        therapeutically effective amount of fospropofol, or a        pharmaceutically acceptable salt thereof, in 300 mL of water at        25° C., results in a solution having a pH of 4.2 or less.    -   Aspect 9. The pharmaceutical dosage form according to aspect 1,        wherein dissolution of an amount of the dosage form containing a        therapeutically effective amount of fospropofol, or a        pharmaceutically acceptable salt thereof, in 300 mL of water at        25° C. results, in a solution having a pH of 4.0 or less.    -   Aspect 10. The pharmaceutical dosage form according to aspect 1,        wherein dissolution of an amount of the dosage form containing a        therapeutically effective amount of fospropofol, or a        pharmaceutically acceptable salt thereof, in 300 mL of 0.1 N HCl        at 37° C., results in release of at least 30% of the fospropofol        from the dosage form within 30 minutes.    -   Aspect 11. The pharmaceutical dosage form according to aspect 1,        wherein the mole ratio of fospropofol, or a pharmaceutically        acceptable salt thereof, to the pharmaceutically acceptable acid        is 3:1 or less.    -   Aspect 12. A method of treating a disease or disorder in subject        in need thereof, said method comprising orally administering to        said subject a pharmaceutical dosage form according to aspect 1.    -   Aspect 13. The method according to aspect 12, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form according to aspect 1 is ascorbic acid.    -   Aspect 14. The method according to aspect 12, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form according to aspect 1 is tartaric acid.    -   Aspect 15. The method according to aspect 12, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form according to aspect 1 is citric acid.    -   Aspect 16. The method according to aspect 12, wherein the        pharmaceutically acceptable acid in said pharmaceutical dosage        form according to aspect 1 is malic acid.    -   Aspect 17. The method according to aspect 12, wherein said        subject is a human.    -   Aspect 18. The method of aspect 12, wherein the disease or        disorder is migraine, acute repetitive seizures, seizure        clusters, neuropathic pain, postherpetic neuralgia, traumatic        brain injury, Alzheimer's disease, epilepsy, anxiety, fragile X        syndrome, post-traumatic stress disorder, lysosomal storage        disorders (Niemann-Pick type C disease), depression (including        post-partum depression), premenstrual dysphoric disorder,        alcohol craving, or smoking cessation.    -   Aspect 19. The method of aspect 18, wherein the disease or        disorder is migraine.    -   Aspect 20. The method of aspect 12, wherein said subject has or        is suspected of having hypochlorhydria or achlorhydria prior to        the administration of the pharmaceutical dosage form according        to aspect 1.    -   Aspect 21. The method according to aspect 20, wherein said        subject has been administered a proton pump inhibitor (PPI)        prior to the administration of the pharmaceutical dosage form        according to aspect 1.    -   Aspect 22. The method of aspect 12, wherein said administration        of the pharmaceutical dosage form according to aspect 1 results        in a propofol Cmax that is greater than a propofol Cmax        resulting from administering fospropofol disodium without        administration of a pharmaceutically acceptable acid.    -   Aspect 23. The method of aspect 22, wherein the propofol Cmax is        at least 1.2 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 24. The method of aspect 23, wherein the propofol Cmax is        at least 3 times greater than a propofol Cmax resulting from        administering fospropofol disodium without administration of the        pharmaceutically acceptable acid.    -   Aspect 25. The method of aspect 12, wherein said administration        of the pharmaceutical dosage form according to aspect 1 results        in a propofol AUC_(∞) that is greater than a propofol AUC_(∞)        resulting from administering fospropofol disodium without        administration of a pharmaceutically acceptable acid.    -   Aspect 26. The method of aspect 25, wherein the propofol AUC_(∞)        is at least 1.5 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.    -   Aspect 27. The method of aspect 26, wherein the propofol AUC_(∞)        is at least 3 times greater than a propofol AUC_(∞) resulting        from administering fospropofol disodium without administration        of a pharmaceutically acceptable acid.

What is claimed is:
 1. A method of treating migraine in a patient inneed thereof, the method comprising orally administering fospropofol, apharmaceutically acceptable salt of fospropofol, or mixtures thereof, tothe patient in one or more doses, wherein the administration results ina Cmax of propofol of at least 50-500 ng/mL, and wherein following theadministration the patient is headache free, has experienced a reductionin headache pain, or is no longer experiencing a most bothersomesymptom.
 2. The method of claim 1, wherein the administration results ina Cmax of propofol of at least 50 ng/mL.
 3. The method of claim 1,wherein the administration results in a Cmax of propofol of at least 75ng/mL.
 4. The method of claim 1, wherein the administration results in aCmax of propofol of at least 100 ng/mL.
 5. The method of claim 1,wherein the administration results in a Cmax of propofol of at least 200ng/mL.
 6. The method of claim 1, wherein the administration results in aCmax of propofol of at least 300 ng/mL.
 7. The method of claim 1,wherein the administration results in a Cmax of propofol of at least 400ng/mL.
 8. The method of claim 1, wherein the administration results in aCmax of propofol of at least 500 ng/mL.
 9. A method of treating migrainein a patient in need thereof, the method comprising orally administeringfospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to the patient in one or more doses, wherein theadministration results in an AUC_(4hr) of propofol of no less than 100ng hr/mL, and wherein following the administration the patient isheadache free, has experienced a reduction in headache pain, or is nolonger experiencing a most bothersome symptom.
 10. The method of claim9, the administration results in an AUC_(4hr) of propofol of no lessthan 200 ng hr/mL.
 11. The method of claim 9, wherein the administrationresults in an AUC_(4hr) of propofol of no less than 300 ng hr/mL. 12.The method of claim 9, wherein the administration results in anAUC_(4hr) of propofol of no less than 400 ng hr/mL.
 13. The method ofclaim 9, wherein the administration results in an AUC_(4hr) of propofolof no less than 500 ng hr/mL.
 14. A method of treating migraine in apatient in need thereof, the method comprising orally administeringfospropofol, a pharmaceutically acceptable salt of fospropofol, ormixtures thereof, to the patient in one or more doses, wherein theadministration results in a Cmax of fospropofol no less than 2000 ng/mL,and wherein following the administration the patient is headache free,has experienced a reduction in headache pain, or is no longerexperiencing a most bothersome symptom.
 15. The method of claim 14,wherein the administration results in a Cmax of fospropofol no less than3000 ng/mL.
 16. The method of claim 14, wherein the administrationresults in a Cmax of fospropofol no less than 4000 ng/mL.
 17. The methodof claim 14, wherein the administration results in a Cmax of fospropofolno less than 5000 ng/mL.
 18. A method of treating migraine in a patientin need thereof, the method comprising orally administering fospropofol,a pharmaceutically acceptable salt of fospropofol, or mixtures thereof,to the patient in one or more doses, wherein the administration resultsin a AUC_(4hr) of fospropofol of no less than 1000 ng hr/mL, and whereinfollowing the administration the patient is headache free, hasexperienced a reduction in headache pain, or is no longer experiencing amost bothersome symptom.
 19. The method of claim 18, wherein theadministration results in an AUC_(4hr) of fospropofol of no less than2000 ng hr/mL.
 20. The method of claim 18, wherein the administrationresults in an AUC_(4hr) of fospropofol of no less than 3000 ng hr/mL.21. The method of claim 1, wherein 2 hours following the administration,the patient is headache free.
 22. The method of claim 1, wherein 2 hoursfollowing the administration, the patient has experienced a reduction inheadache pain.
 23. The method of claim 1, wherein 2 hours following theadministration, the patient is no longer experiencing a most bothersomesymptom.
 24. The method of claim 9, wherein 2 hours following theadministration, the patient is headache free.
 25. The method of claim 9,wherein 2 hours following the administration, the patient hasexperienced a reduction in headache pain.
 26. The method of claim 9,wherein 2 hours following the administration, the patient is no longerexperiencing a most bothersome symptom.
 27. The method of claim 14,wherein 2 hours following the administration, the patient is headachefree.
 28. The method of claim 14, wherein 2 hours following theadministration, the patient has experienced a reduction in headachepain.
 29. The method of claim 14, wherein 2 hours following theadministration, the patient is no longer experiencing a most bothersomesymptom.
 30. The method of claim 18, wherein 2 hours following theadministration, the patient is headache free.
 31. The method of claim18, wherein 2 hours following the administration, the patient hasexperienced a reduction in headache pain.
 32. The method of claim 18,wherein 2 hours following the administration, the patient is no longerexperiencing a most bothersome symptom.